N-cyano-7-azanorbornane derivatives and uses thereof

ABSTRACT

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising a compound of the invention, a method for manufacturing compounds of the invention and therapeutic uses thereof.

The present invention relates generally to a class of substitutedN-cyano-7-azanorbornanes with activity as inhibitors of deubiquitinatingenzymes, in particular, ubiquitin C-terminal hydrolase 30 or ubiquitinspecific peptidase 30 (USP30), uses thereof, processes for thepreparation thereof and compositions comprising said inhibitors. Theseinhibitors have utility in a variety of therapeutic areas includingcancer, conditions involving mitochondrial dysfunction andneurodegenerative diseases.

BACKGROUND OF THE INVENTION

Ubiquitin is a small protein consisting of 76 amino acids that isimportant for the regulation of protein function in a cell.Ubiquitylation and deubiquitylation are enzymatically mediated processesby which ubiquitin is covalently bound or cleaved from a target proteinby deubiquitylating enzymes (DUBs), of which there are approximately 95DUBs in human cells, divided into sub-families based on sequencehomology. The USP family are characterized by their common Cys and Hisboxes which contain Cys and His residues critical for their DUBactivities. The ubiquitylation and deubiquitylation processes have beenimplicated in the regulation of many cellular functions including cellcycle progression, apoptosis, modification of cell surface receptors,regulation of DNA transcription and DNA repair. Thus, the ubiquitinsystem has been implicated in the pathogenesis of numerous diseasestates including inflammation, viral infection, metabolic dysfunction,CNS disorders and oncogenesis.

Ubiquitin is a master regulator of mitochondrial dynamics. Mitochondriaare dynamic organelles whose biogenesis, fusion and fission events areregulated by the post-translational regulation via ubiquitylation ofmany key factors such as mitofusins. While ubiquitin ligases such asparkin are known to ubiquity late a number of mitochondrial proteins,until recently deubiquitylating enzymes remained elusive. USP30 is a 517amino acid protein which is found on the mitochondrial outer membrane(Nakamura et al., Mol Biol (2008) 19:1903-11). It is the soledeubiquitylating enzyme bearing a mitochondrial localization signal andhas been shown to debuiquitylate a number of mitochondrial proteins. Ithas been demonstrated that USP30 opposes parkin-mediated mitophagy andthat reduction of USP30 activity can rescue parkin-mediated defects inmitophagy.

Mitochondrial dysfunction may be defined as diminished mitochondrialcontent (mitophagy or mitochondrial biogenesis), as a decrease inmitochondrial activity and oxidative phosphorylation, but also asmodulation of reactive oxygen species (ROS) generation. Hence a role formitochondrial dysfunction has been ascribed to a very large number ofaging processes and pathologies including but not limited toneurodegenerative diseases, cancer, diabetes, metabolic disorders,cardiovascular disease, psychiatric disease and osteoarthritis.

Mitochondrial dysfunction has been implicated in the etiology ofParkinson's disease. Human genetic evidence for mitochondrialdysfunction has come from studies of familial forms of Parkinson'sdisease, which have identified the autosomal recessive genes PARK2 andPINK1 encoding Parkin ubiquitin ligase and phosphatase and tensinhomolog-induced putative kinase 1 (PINK1) protein kinase (Hauser, D. N.,and Hastings, T. G. (2013). Neurobiol Dis 51, 35-42). These genes havebeen linked to regulation of mitochondrial quality control by a processcalled mitophagy (Misgeld, T., and Schwarz, T. L. (2017) Neuron 96,651-66; Pickrell and Youle, (2015) Neuron 85, 257-273; Trinh and Farter,(2013) Nat Rev Neurol 9, 445-454). In healthy mitochondria PINK1 isimported and degraded by mitochondrial proteases. However, onmitochondrial damage, PINK1 accumulates on the surface of the outermitochondrial membrane, where it recruits Parkin, Relocated Parkinsubsequently ubiquitylates several mitochondrial proteins, creating asignal for the removal of the damaged mitochondrion by mitophagy.Parkinson's disease-associated mutations in PINK1 or PARK2 impairrecruitment of parkin, mitochondrial ubiquitination and mitophagy(Archer, S. L. (2013). N Engl J Med 369, 2236-2251). Enhancing mitophagyvia the PINK1-Parkin pathway is proposed to be a therapeutic target fordisease modification in Parkinson's disease. An additional role for thePINK1-Parkin pathway in suppressing mitochondrial antigen presentationand T-cell mediated immune responses has recently been discovered andmay also play a role in Parkinson's disease pathology (Matheoud et al.,(2016) Cell 166, 314-327).

From a library of 100 deubiquitinating enzymes (DUBs), Genentechidentified USP30 as one of two DUBS significantly preventingmitochondrial loss after administration of the protonophore carbonylcyanide 3-chlorophenylhydrazone (CCCP) to Parkin overexpressing HEK293cells (Bingol et al., (2014) Nature 510, 370-375). USP30 is the onlymitochondria-anchored DUB and was further validated as counter player inParkin-mediated mitophagy in Drosophila (Bingol et al., 2014). USP30hinders the build-up of ubiquitin chains on mitochondrial proteins,thereby preventing inappropriate mitophagy in healthy conditions(Cunningham et al., (2015) Nat Cell Biol 17, 160-169). When mitochondriaare damaged, Parkin is recruited to the membrane and highly activated,overwhelming USP30 and shifting the equilibrium to a buildup ofubiquitin chains that activate mitophagic pathways. In the case ofpathogenic PARK2 mutations or otherwise compromised Parkin activity, theligase is unable to overcome USP30 mediated deubiquitination and thuscannot properly activate mitophagy. Therefore, inhibition of USP30 couldbe a therapeutic treatment for Parkinson's patients that have reducedfunction of the PINK1-Parkin mitophagy pathway.

A series of cyano-substituted heterocycles are disclosed asdeubiquitinating enzyme inhibitors in WO2016/046530, WO2016/156816,WO2017/009650, WO2017/093718, WO2017/103614 and WO2018/060742. Itremains desirable to provide additional deubiquitinating enzymeinhibitors which provide selectivity for USP30 over other cysteineproteases such as other DUBs and/or Cathepsins.

Thus, new approaches are needed to modulate USP30 activity in theprevention and/or treatment of mitochondrial dysfunction andneurodegenerative diseases. There remains a need for agents that exploitdifferent mechanisms of action and may have better outcomes in terms ofrelief of symptoms, safety, and patient mortality, both short-term andlong-term.

SUMMARY OF THE INVENTION

The present invention provides compounds which modulate USP30 proteins,and more specifically inhibit USP30. The present invention provides, inone aspect, substituted N-cyano-7-azanorbornane compounds which inhibitUSP30 activity. Certain compounds provided herein provide selectiveinhibition of USP30 activity compared to inhibition of Cathepsin K or Sand/or other DUB enzymes. Certain compounds provided by thespecification at least 10-fold greater USP30 inhibition compared toCathepsin K or S or other DUB enzymes as measured by IC50. In certainaspects, the compounds of the invention are at least 20-fold or 50-foldselective inhibitors of USP30 compared to Cathepsin K or S or other DUBenzymes. Inhibition of USP30 activity may be particularly desirable inthe treatment or prevention of a variety of diseases includingmitochondrial dysfunction and neurodegenerative diseases.

The invention provides, in one aspect, substitutedN-cyano-7-azanorbornane compounds which modulate USP30 enzyme activity.Preferably, the substituted N-cyano-7-azanorbornane compounds of theinvention are USP30 inhibitors.

The substituted benzimidazole compounds of the invention are compoundsand salts according to Formula (I):

Also provided is a pharmaceutical composition comprising apharmaceutically acceptable excipient, carrier or adjuvant and at leastone compound of Formula (I) or subformulae thereof. Pharmaceuticalcompositions provided by the invention are suitable for use in thetreatment of disease modulated by USP30 activity. In certain aspects thepharmaceutical compositions of the invention are suitable for use in thetreatment of diseases associated with mitochondrial dysregulation, e.g.,treatment of a disease or disorder mediated by USP30 is selected fromthe group consisting of a CNS disorder, neurodegenerative disease,multiple sclerosis, mitochondrial myopathy, encephalopathy, lacticacidosis, stroke-like episodes, Leber's hereditary optic neuropathy,cancer, neuropathy, ataxia, retinitis pigmentosa, maternally inheritedLeigh syndrome, Danon disease, diabetes, diabetic nephropathy, metabolicdisorders, heart failure, ischemic heart disease leading to myocardialinfarction, psychiatric disease, schizophrenia, multiple sulfatasedeficiency, mucolipidosis II, mucolipidosis III, mucolipidosis IV,GMI-gangliosidosis, neuronal ceroid-lipofuscinoses, Alpers disease.Barth syndrome, Beta-oxidation defects, carnitine-acyl-carnitinedeficiency, carnitine deficiency, creatine deficiency syndromes,co-enzyme Q10 deficiency, complex I deficiency, complex II deficiency,complex III deficiency, complex IV deficiency, complex V deficiency, COXdeficiency, chronic progressive external ophthalmoplegia syndrome, CPT Ideficiency, CPT II deficiency, glutaric aciduria type II, Kearns-Sayresyndrome, lactic acidosis, long-chain acyl-CoA dehydrogenase deficiency,Leigh disease or syndrome, lethal infantile cardiomyopathy, Luftdisease, glutaric aciduria type II, medium-chain acyl-CoA dehydrogenasedeficiency, myoclonic epilepsy and ragged-red fiber syndrome,mitochondrial cytopathy, mitochondrial recessive ataxia syndrome,mitochondrial DNA depletion syndrome, myoneurogastointestinal disorderand encephalopathy, Stiff Person syndrome, pyruvate dehydrogenasedeficiency, pyruvate carboxylase deficiency. POLG mutations,medium/short-chain 3-hydroxy acyl-CoA dehydrogenase deficiency, verylong-chain acyl-CoA dehydrogenase deficiency, and age-dependent declinein cognitive function and muscle strength.

Also provided is a packaged pharmaceutical composition, comprising apharmaceutical composition comprising a pharmaceutically acceptableexcipient, carrier or adjuvant and at least one compound of formula (I)or subformulae thereof, and instructions for using the composition totreat a patient suffering from a disease mediated by USP30 activity. Incertain instances, the patient is suffering from mitochondrialdysregulation, e.g., treatment of a disease or disorder mediated byUSP30 is selected from the group consisting of a CNS disorder,neurodegenerative disease, multiple sclerosis, mitochondrial myopathy,encephalopathy, lactic acidosis, stroke-like episodes, Leber'shereditary optic neuropathy, cancer, neuropathy, ataxia, retinitispigmentosa, maternally inherited Leigh syndrome. Danon disease,diabetes, diabetic nephropathy, metabolic disorders, heart failure,ischemic heart disease leading to myocardial infarction, psychiatricdisease, schizophrenia, multiple sulfatase deficiency, mucolipidosis II,mucolipidosis III, mucolipidosis IV, GMI-gangliosidosis, neuronalceroid-lipofuscinoses, Alpers disease, Barth syndrome, Beta-oxidationdefects, carnitine-acyl-carnitine deficiency, carnitine deficiency,creatine deficiency syndromes, co-enzyme Q10 deficiency, complex Ideficiency, complex II deficiency, complex III deficiency, complex IVdeficiency, complex V deficiency, COX deficiency, chronic progressiveexternal ophthalmoplegia syndrome, CPT I deficiency. CPT II deficiency,glutaric aciduria type II, Kearns-Sayre syndrome, lactic acidosis,long-chain acyl-CoA dehydrogenase deficiency, Leigh disease or syndrome,lethal infantile cardiomyopathy, Luft disease, glutaric aciduria typeII, medium-chain acyl-CoA dehydrogenase deficiency, myoclonic epilepsyand ragged-red fiber syndrome, mitochondrial cytopathy, mitochondrialrecessive ataxia syndrome, mitochondrial DNA depletion syndrome,myoneurogastointestinal disorder and encephalopathy, Stiff Personsyndrome, pyruvate dehydrogenase deficiency, pyruvate carboxylasedeficiency, POLG mutations, medium/short-chain 3-hydroxy acyl-CoAdehydrogenase deficiency, very long-chain acyl-CoA dehydrogenasedeficiency, and age-dependent decline in cognitive function and musclestrength.

Also provided is a method of treating or preventing disease in a mammalwhich method comprises administering to a mammal in need thereof atherapeutically effective amount of at least one compound of formula (I)or subformulae thereof or a pharmaceutical composition comprising apharmaceutically acceptable excipient, carrier or adjuvant and at leastone compound of formula (I) or subformulae thereof.

Also provided is a method for modulating USP30 activity in a mammal,which method comprises administering to the mammal in need thereof atherapeutically effective amount of at least one compound of formula (I)or subformulae thereof or a pharmaceutical composition comprising apharmaceutically acceptable excipient, carrier or adjuvant and at leastone compound of formula (I) or subformulae thereof. Another aspect ofthe invention relates to a method of treating a mitochondrialdysregulation mediated disease or disorder, the method comprisingadministering a USP30 inhibitor of the invention to a patient in need oftherapy. In certain embodiments, the mitochondrial dysregulationsmediated disease or disorder is selected from CNS disorder,neurodegenerative disease, multiple sclerosis, mitochondrial myopathy,encephalopathy, lactic acidosis, stroke-like episodes, Leber'shereditary optic neuropathy, cancer, neuropathy, ataxia, retinitispigmentosa, maternally inherited Leigh syndrome, Danon disease,diabetes, diabetic nephropathy, metabolic disorders, heart failure,ischemic heart disease leading to myocardial infarction, psychiatricdisease, schizophrenia, multiple sulfatase deficiency, mucolipidosis II,mucolipidosis III, mucolipidosis IV, GMI-gangliosidosis, neuronalceroid-lipofuscinoses, Alpers disease, Barth syndrome. Beta-oxidationdefects, carnitine-acyl-carnitine deficiency, carnitine deficiency,creatine deficiency syndromes, co-enzyme Q10 deficiency, complex Ideficiency, complex II deficiency, complex III deficiency, complex IVdeficiency, complex V deficiency, COX deficiency, chronic progressiveexternal ophthalmoplegia syndrome, CPT I deficiency, CPT II deficiency,glutaric aciduria type II, Kearns-Sayre syndrome, lactic acidosis,long-chain acyl-CoA dehydrogenase deficiency. Leigh disease or syndrome,lethal infantile cardiomyopathy, Luft disease, glutaric aciduria typeII, medium-chain acyl-CoA dehydrogenase deficiency, myoclonic epilepsyand ragged-red fiber syndrome, mitochondrial cytopathy, mitochondrialrecessive ataxia syndrome, mitochondrial DNA depletion syndrome,myoneurogastointestinal disorder and encephalopathy, Stiff Personsyndrome, pyruvate dehydrogenase deficiency, pyruvate carboxylasedeficiency. POLG mutations, medium/short-chain 3-hydroxyacyl-CoAdehydrogenase deficiency, very long-chain acyl-CoA dehydrogenasedeficiency, and age-dependent decline in cognitive function and musclestrength.

Also provided is the use, in the manufacture of a medicament fortreating or preventing disease mediated by USP30 activity, of at leastone compound of formula I or subformulae thereof.

Also provided are methods of preparing compounds formula I orsubformulae thereof.

Other aspects and embodiments will be apparent to those skilled in theart form the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The invention related generally to compounds of Formula I and salts andtautomers thereof which modulate USP30 protein activity and moreparticularly inhibit USP30 protein activity. In particular, theinvention relates to compounds which selectively inhibit USP30 proteinactivity. Certain compounds provided herein selectively inhibit USP30 incomparison to activity against other cysteine proteases such as DUBproteins (including USP45) and/or Cathepsin K or S. Certain compoundsprovided herein offer at least 10-fold selectivity for USP30 inhibitioncompared to other cysteine proteases. Other compounds provided hereinoffer at least 20-fold, 50-fold or 100-fold selectivity for USP30inhibition compared to other cysteine proteases. While not wishing to bebound by theory, it is believed that selective inhibition of USP30activity may be particularly desirable for the treatment of diseases ordisorders associated with mitochondrial dysfunction.

In a first embodiment, the disclosure provides a compound or saltthereof, the compound according to the Formula (I):

Wherein

D is (CR¹R²)_(r);

r is 1 or 2;

Each of R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ is independently selected at eachoccurrence from hydrogen, halogen, C₁₋₆alkyl, C₁-C₄alkoxy orC₃-C₆cycloalkyl; or

R⁴ and R⁶ taken in combination form a fused three to six-membercycloalkyl ring; or

R⁴ and R⁵ taken in combination form a spirocyclic three to six-membercycloalkyl ring;

R⁶ and R⁷ taken in combination form a spirocyclic three to six-membercycloalkyl ring;

R⁸ is independently selected from hydrogen or C₁-C₄alkyl;

L is a bond or a divalent linker selected from —C(O)—, —C(O)N(R^(B))—,—N(R^(B))C(O)—, —N(R^(B))C(O)N(R^(B))—, —N(R^(B))S(O)_(p)—,—S(O)_(p)N(R^(B))—, —[C(R^(A))₂]_(q)C(O)N(R^(B))—,—C(O)N(R^(B))[C(R^(A))₂]_(q)—, —N(R^(B))C(O)N(R^(B))[C(R^(A))₂]_(q)—,—[C(R^(A))₂)]_(q)N(R^(B))C(O)N(R^(B))—,—C(R^(A))₂N(R^(C))C(R^(A))₂C(O)N(R^(B))—,—N(R^(C))C(R^(A))₂C(O)N(R^(B))—, —C(O)N(R^(C))C(R^(A))₂C(O)N(R^(B))—,—N(R^(C))C(O)C(O)N(R^(B))—, —OC(R^(A))₂C(O)N(R^(B))— or—SC(R^(A))₂C(O)N(R^(B))—, wherein L is attached to the azanorbornane bythe right most atom;

p is selected at each occurrence from 0, 1 or 2;

q is 1, 2 or 3;

R^(A) is independently, at each occurrence, hydrogen, C₁-C₄alkyl,haloC₁-C₄alkyl and haloC₁-C₄alkoxy, or C(R^(A))₂, taken in combinationforms —C(O)— or 1,1-cyclopropandiyl;

R^(B) is hydrogen or C₁-C₄alkyl;

R^(C) is hydrogen, C₁-C₄alkyl or —C(R^(A))₂-A-B;

A is a divalent moiety selected from C₂-C₆alkenylene, phenylene,naphthylene, 5 to 13 member heteroarylene comprising one ring N, O or Satom and 0 or 1 additional ring nitrogen atom, or saturated or partiallyunsaturated 4 to 13 member monocyclic, bicyclic or tricyclic carbocycleor heterocycle comprising one ring N, O or S atom and 0, 1 or 2additional ring nitrogen atoms S, each of which is optionallysubstituted with 0 to 4 substituents selected from halogen, hydroxy,oxo, amino, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,C₃-C₇cycloalkyl, C₃-C₇cycloalkoxy, C₃-C₇cycloalkylC₁-C₄alkyl,C₃-C₇cycloalkylC₁-C₄alkoxy, haloC₁-C₆alkyl, haloC₁-C₆alkoxy;

B is hydrogen, halogen, hydroxy, amino. C₁-C₆alkyl, haloC₁-C₆alkyl,hydroxyC₁-C₆alkyl, cyanoC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, haloC₁-C₆alkoxy, C₁-C₆cycloalkyl, halo C₃-C₇cycloalkyl,cyanoC₃-C₇cycloalkyl, C₃-C₇cycloalkylC₁-C₆alkyl,cyanoC₃-C₇cycloalkylC₁-C₆alkyl, C(O)C₁-C₆alkyl, C(O)C₃-C₇cycloalkyl,C(O)C₁-C₆alkyl, C(O)C₃-C₇cycloalkyl, NR⁹R¹⁰, OR¹¹, C(O)NR⁹R¹⁰,N(R¹⁰)C(O)R¹², phenyl, aralkyl, heteroaralkyl, 5, 6, 9 or 10 memberheteroaryl or 4 to 8 mender monocyclic or bicyclic heterocycle, whereineach heteroaryl or heterocycle has one ring N, O or S atom and 0.1 or 2additional ring nitrogen atoms, which phenyl, aralkyl, heteroaralkyl,heteroaryl or heterocycle is optionally substituted with 0 to 4 groupsindependently selected from the group consisting of halogen, hydroxy,amino, mono- and di-C₁-C₆alkylamino, cyano, C₁-C₆alkyl, C₂-C₆alkenyl,C₁-C₆alkynyl, C₁-C₆alkoxy, halo C₁-C₆alkyl, halo C₁-C₆alkoxy,C₃-C₆cycloalkyl, phenyl, 5 or 6 member heteroaryl having one ring N, Oor S atom and 0, 1 or 2 additional ring nitrogen atoms, —C(O)NR⁹R¹⁰,C(O)R⁹, CO₂R⁹, and S(O)_(n)R⁹, and where each heterocycle is optionallysubstituted with oxo;

R⁹ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,halo C₁-C₆alkyl, halo C₁-C₆alkoxy, C₃-C₆cycloalkyl, aralkyl whicharalkyl is substituted with 1 to 4 substituents independently selectedfrom halogen, C₁-C₄alkyl, C₃-C₆cycloalkyl or 1,1-cyclopropandiyl;

R¹⁰ is hydrogen or C₁-C₆alkyl;

R¹¹ is C₁-C₆cycloalkyl, phenyl or 5 or 6-member heteroaryl having onering nitrogen atom and 0 or 1 additional ring heteroatoms selected fromN, O or S, which phenyl or heteroaryl is optionally substituted with 0,1, 2, or 3 groups independently selected from halogen, cyano,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, halo C₁-C₆alkyl,halo C₁-C₆alkoxy, C₃-C₆cycloalkyl; and

R¹² is selected from C₁-C₆alkyl, C₁-C₆alkoxy, halo C₁-C₆alkyl, haloC₁-C₆alkoxy, C₃-C₆cycloalkyl, phenyl or 5 or 6 member heteroaryl havingone ring nitrogen atom and 0 or 1 additional ring heteroatoms selectedfrom N, O or S, which phenyl or heteroaryl is optionally substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, hydroxy,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, halo C₁-C₆alkyl,halo C₁-C₆alkoxy, C₃-C₆cycloalkyl.

In certain aspects of first embodiment, the disclosure provides acompound or salt thereof, the compound according to the Formula (I):

Wherein

D is (CR¹R²)_(r);

r is 1 or 2;

Each of R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ is independently selected at eachoccurrence from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy orC₃-C₆cycloalkyl; or

R⁴ and R⁶ taken in combination form a fused three to six-membercycloalkyl ring; or

R⁴ and R⁵ taken in combination form a spirocyclic three to six-membercycloalkyl ring;

R⁶ and R⁷ taken in combination form a spirocyclic three to six-membercycloalkyl ring;

R⁸ is independently selected from hydrogen or C₁-C₄alkyl;

L is a bond or a divalent linker selected from —C(O)—, —C(O)N(R^(B))—,—N(R^(B))C(O)—, —N(R^(B))C(O)N(R^(B))—, —N(R^(B))S(O)_(p)—,—S(O)_(p)N(R^(B))—, —[C(R^(A))₂]_(q)C(O)N(R^(B))—,—C(O)N(R^(B))[C(R^(A))₂]_(q)—, C(O)N(R^(B))—[C(R^(A))₂]_(q)—,—C(R^(A))₂N(R^(C))C(R^(A))₂C(O)N(R^(B))—,—N(R^(C))C(R^(A))₂C(O)N(R^(B))—, —C(O)N(R^(C))C(R^(A))₂C(O)N(R^(B))—,—N(R^(C))C(O)C(O)N(R^(B))—, —OC(R^(A))₂C(O)N(R^(B))— or—SC(R^(A))₂C(O)N(R^(B))—, wherein L is attached to the azanorbornane bythe right most atom;

p is selected at each occurrence from 0, 1 or 2:

q is 1, 2 or 3;

R^(A) is independently, at each occurrence, hydrogen or C₁-C₄alkyl, orC(R^(A))₂, taken in combination forms —C(O)—;

R^(B) is hydrogen or C₁-C₄alkyl;

R^(C) is hydrogen, C₁-C₄alkyl or —C(R^(A))₂-A-B;

A is a divalent moiety selected from phenylene, naphthylene, 5, 6, 9 or10 member heteroarylene comprising one ring nitrogen atom and 0 or 1additional ring heteroatoms selected from N, O or S, or saturated orpartially unsaturated 5 to 11 member monocyclic or bicyclic carbocycleor heterocycle comprising one or two ring nitrogen atoms and 0 or 1additional ring heteroatoms selected from N, O or S, each of which isoptionally substituted with 0 to 4 substituents selected from halogen,hydroxy, oxo, amino, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, C₃-C₇cycloalkyl, C₃-C₇cycloalkoxy,C₃-C₇cycloalkylC₁-C₄alkyl, C₃-C₇cycloalkylC₁-C₄alkoxy, haloC₁-C₆alkyland haloC₁-C₆alkoxy.

B is hydrogen, halogen, hydroxy, amino, C₁-C₆alkyl, haloC₁-C₆alkylC₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, haloC₁-C₆alkoxy,C₃-C₇cycloalkyl, C(O)C₁-C₆alkyl, C(O)C₃-C₇cycloalkyl, NR⁹R¹⁰, OR¹¹,C(O)NR⁹R¹⁰, N(R¹⁰)C(O)R¹², phenyl, 5, 6, 9 or 10 member heteroaryl or 4to 7 member heterocycle, wherein each heteroaryl or heterocycle has onering N, O or S atom and 0, 1 or 2 additional ring nitrogen atom, whichphenyl, heteroaryl or heterocycle is optionally substituted with 0 to 4groups independently selected from the group consisting of halogen,hydroxy, amino, mono- and di-C₁-C₆alkylamino, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, halo C₁-C₆alkyl, haloC₁-C₆alkoxy, C₃-C₆cycloalkyl, —C(O)NR⁹R¹⁰, C(O)R⁹, CO₂R⁹, S(O)_(n)R⁹;

R⁹ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,halo C₁-C₆alkyl, halo C₁-C₆alkoxy, C₃-C₆cycloalkyl.

R¹⁰ is hydrogen or C₁-C₆alkyl;

R¹¹ is phenyl or S or 6-member heteroaryl having one ring nitrogen atomand 0 or 1 additional ring heteroatoms selected from N, O or S, whichphenyl or heteroaryl is optionally substituted with 0, 1, 2, or 3 groupsindependently selected from C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, halo C₁-C₆alkyl, halo C₁-C₆alkoxy, C₁-C₆cycloalkyl; and

R¹² is selected from C₁-C₆alkyl, C₁-C₆alkoxy, halo C₁-C₆alkyl, haloC₁-C₆alkoxy, C₃-C₆cycloalkyl, phenyl or 5 or 6 member heteroaryl havingone ring nitrogen atom and 0 or 1 additional ring heteroatoms selectedfrom N, O or S, which phenyl or heteroaryl is optionally substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, hydroxy,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, halo C₁-C₆alkyl,halo C₁-C₆alkoxy, C₃-C₆cycloalkyl.

In a second embodiment, the disclosure provides a compound of the firstembodiment which compound is represented by Formula Ia:

In a third embodiment, the disclosure provides a compound of the firstor second embodiment, wherein L is —C(O)N(R^(B))— and R^(B) is hydrogen,methyl or ethyl.

In a fourth embodiment, the disclosure provides a compound of the thirdembodiment which represented by Formula II:

In a filth embodiment, the disclosure provides a compound of any one ofthe first to fourth embodiments in which the azanorbornane is in endoorientation.

In a sixth embodiment, the disclosure provides a compound of any one ofthe first to fifth embodiments which compound is represented by FormulaII-a or II-b:

In a seventh embodiment, the disclosure provides a compound of any oneof the first to sixth embodiments in which -A-B is selected from thegroup consisting of

Wherein * represents point of attachment to L;

Each occurrence of Q is independently selected from CR¹³ or N;

R¹³ is 0, 1, 2 or 3 independently selected from hydrogen, halogen,C₁-C₆alkyl, C₁-C₆alkoxy, haloC₁-C₆alkyl, haloC₁-C₆alkoxy,C₃-C₆cycloalkyl, C₃-C₆cycloalkyC₁-C₄alkoxy, orC₃-C₆cycloalkylC₁-C₄alkyl.

In an eighth embodiment, the disclosure provides a compound of seventhembodiment which is a compound represented by Formula III:

Wherein

R¹³ is 0, 1, 2 or 3 independently selected from hydrogen, halogen,hydroxy, amino, C₁-C₆alkyl, and C₁-C₆alkoxy;

X is CH, CH₂, CH₂CH₂ or N;

Y is CH, CH₂, CH₂CH₂, N or O;

B is hydrogen, halogen, hydroxy, amino, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆cycloalkyl, C(O)C₁-C₄alkyl C(O)C₃-C₅cycloalkyl,C(O)OC₁-C₄alkyl, C(O)NHC₁C₄alkyl or C(O)NHC₃-C₆cycloalkyl phenyl, 5 or 6member heteroaryl or 5 or 6 member heterocycle, wherein each heteroarylor heterocycle has one ring N, O or S atom and 0, 1 or 2 additional ringnitrogen atom, which phenyl, heteroaryl or heterocycle is optionallysubstituted with 0 to 4 groups independently-selected from the groupconsisting of halogen, hydroxy, amino, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆alkoxy, halo C₁-C₆alkyl, halo C₁-C₆alkoxy,C₃-C₆cycloalkyl, cyanoC₁-C₄alkyl cyanoC₃-C₅cycloalkyl, —C(O)NR⁹R¹⁰,C(O)R⁹, CO₂R⁹, S(O)_(n)R⁹;

R⁹ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,halo C₁-C₆alkyl, halo C₁-C₆alkoxy, C₃-C₆cycloalkyl; and

R¹⁰ is hydrogen or C₁-C₆alkyl.

In certain aspects of the eighth embodiment B is phenyl, 5 or 6 memberheteroaryl or 5 or 6 member heterocycle, wherein each heteroaryl orheterocycle one ring N, O or S atom and 0, 1 or 2 additional tingnitrogen atom, which phenyl, heteroaryl or heterocycle is optionallysubstituted with 0 to 4 groups independently selected from the groupconsisting of halogen, hydroxy, amino, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆alkoxy, halo C₁-C₆alkyl, halo C₁-C₆alkoxy,C₁-C₆cycloalkyl, cyanoC₁-C₄alkyl, cyanoC₃-C₅cycloalkyl, —C(O)NR⁹R¹⁰,C(O)R⁹, CO₂R⁹ and S(O)_(n)R⁹.

In certain other aspects of the eighth embodiment, B is phenyl, 5 or 6member heteroaryl or 5 or 6 member heterocycle, wherein each heteroarylor heterocycle one ring N, O or S atom and 0, 1 or 2 additional ringnitrogen atom, which phenyl, heteroaryl or heterocycle is optionallysubstituted with 0 to 3 groups independently selected from the groupconsisting of halogen, C₁-C₆alkyl, C₁-C₆alkoxy, halo C₁-C₆alkyl,haloC₁-C₆alkoxy, C₃-C₆cycloalkyl, cyanoC₁-C₄alkyl andcyanoC₃-C₅cycloalkyl.

In certain other aspects of the eighth embodiment, B is phenyl, 5 or 6member heteroaryl or 5 or 6 member heterocycle, wherein each heteroarylor heterocycle one ring N, O or S atom and 0, 1 or 2 additional ringnitrogen atom, which phenyl, heteroaryl or heterocycle is optionallysubstituted with 0 to 4 groups independently selected from the groupconsisting of halogen, hydroxy, amino, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆alkoxy, halo C₁-C₆alkyl, halo C₁-C₆alkoxy,C₃-C₆cycloalkyl, —C(O)NR⁹R¹⁰, C(O)R⁹, CO₂R⁹ and S(O)_(n)R⁹.

In a ninth embodiment, the disclosure provides a compound of eighthembodiment which is a compound represented by Formula III-a or FormulaIII-b:

In a tenth embodiment, the disclosure provides a compound of eighthembodiment which is a compound represented by Formula (III-c):

Wherein

R¹³ is selected at each occurrence from the group consisting ofhydrogen, C₁-C₄alkyl, halogen, C₁-C₄alkoxy.

In an eleventh embodiment, the disclosure provides a compound of eighthembodiment which is a compound represented by Formula III-d or FormulaIII-e:

In a twelfth embodiment, the disclosure provides a compound of any oneof the sixth to eleventh embodiment in which compound B is phenyl,pyridyl, pyrimidinyl or pyrazinyl each of which is optionallysubstituted with 0, 1, or 2 independently selected from C₁-C₄alkyl orC₃-C₅cycloalkyl; or

B is C₁-C₆alkyl, C₃-C₆cycloalkyl, C(O)C₁-C₄alkyl, C(O)OC₃-C₅cycloalkyl,C(O)OC₁-C₄alkyl, C(O)NHC₁C₄alkyl or C(O)NHC₃-C₆cycloalkyl.

In a thirteenth embodiment the disclosure provides a compound of thesixth embodiment, which compound is represented by Formula IV:

Wherein R⁴ and R⁶ are each independently hydrogen or methyl;

or R⁴ and R⁶, taken in combination form a fused cyclopropyl ring;

R^(B) is hydrogen or methyl;

Z is independently selected at each occurrence from CH or N;

W is CR¹⁴ or N, wherein 0, 1, or 2 occurrences of W and Z is N andremainder is C;

R¹³ is hydrogen, C₁-C₄alkyl or C₃-C₅cycloalkyl;

R¹⁴ is independently selected at each occurrence from hydrogen,C₁-C₄alkyl, C₃-C₅cycloalkyl, cyanoC₁-C₄alkyl and cyanoC₃-C₅cycloalkyl;

X and Y are each CH₂, or

X and Y are each selected from CH or N such that at least one of X and Yis CH.

In a fourteenth embodiment, the disclosure provides a compound of thethirteenth embodiment in which at least one occurrence of either R¹³ orR¹⁴ is not hydrogen.

In certain aspects of the fourteenth embodiment, one occurrence of R¹⁴is hydrogen and one occurrence of R¹⁴ is cyanoC₁-C₄alkyl orcyanoC₃-C₅cycloalkyl.

In certain other aspects of the fourteenth embodiment, R¹⁴ isindependently selected at each occurrence from hydrogen, C₁-C₄alkyl, orC₃-C₅cycloalkyl.

In a fifteenth embodiment, the disclosure provides a compound of thethirteenth or fourteenth embodiment wherein the azanorbornane is in theendo conformation.

In a sixteenth embodiment, the disclosure provides a compound of any oneof the thirteenth to fifteenth embodiment, which compound is representedby Formula IV-a or Formula IV-b:

In a seventeenth embodiment the disclosure provides a compound of anyone of the fifth to eighth embodiment, which compound is represented byFormula V:

Wherein R⁴ and R⁶ are each independently hydrogen or methyl;

or R⁴ and R⁶, taken in combination form a fused cyclopropyl ring;

R⁸ is hydrogen or methyl;

R¹⁵ is C₁-C₄alkyl, C₁-C₄alkoxy, C₃-C₅cycloalkyl, C₃-C₅cycloalkyloxy,C₃-C₅cycloalkylC₁-C₄alkyl, C₃-C₅cycloalkylC₁-C₄alkoxy;

X and Y are each CH₂; or

X and Y are each selected from CH or N such that at least one of X and Yis CH.

In an eighteenth embodiment, the disclosure provides a compound of theseventeenth embodiment wherein the azanorbornane is in the endoconformation.

In a nineteenth embodiment, the disclosure provides a compound of theseventeenth or eighteenth embodiment, wherein the compound isrepresented by Formula V-a or Formula V-b:

In a twentieth embodiment, the disclosure provides a compound of thefirst or second embodiment wherein the compound according to theformula: (VI)

Wherein

G is O, S, N(R^(C)), *—C(O)N(R^(C)) or *—(CH₂)N(R^(C)), wherein the *represents attachment to B-A-;

R^(C) is hydrogen, C₁-C₄alkyl or —CH₂-A-B;

A is phenyl, naphthylene, 5 or 6-member heteroaryl comprising one ringnitrogen atom and 0 or 1 additional ring heteroatoms selected from N, Oor S, each of which is optionally substituted with 0 to 4 substituentsselected from halogen, hydroxy, amino, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆alkoxy, halo C₁-C₆alkyl, and halo C₁-C₆alkoxy;

B is hydrogen, halogen, hydroxy, amino, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl, C(O)C₁-C₆alkyl,C(O)C₃-C₆cycloakyl, C(O)NR⁹R¹⁰, phenyl, 5 or 6 member heteroaryl or 5 or6 member heterocycle, wherein each heteroaryl or heterocycle has onering N, O or S atom and 0, 1 or 2 additional ring nitrogen atom, whichphenyl, heteroaryl or heterocycle is optionally substituted with 0 to 4groups independently selected from the group consisting of halogen,hydroxy, amino, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,halo C₁-C₆alkyl, halo C₁-C₆alkoxy, C₃-C₆cycloalkyl, —C(O)NR⁹R¹⁰, C(O)R⁹,CO₂R⁹, S(O)_(n)R⁹.

In a twenty-first embodiment, the disclosure provides compounds of thetwentieth embodiment in which G is O, S, N(H) or *C(O)N(H), whereinthe * represents attachment to B-A-;

A is phenyl, naphthyl or 5 or 6-member heteroaryl, each of which isoptionally substituted with 0, 1, 2, 3, or 4 groups independentlyselected from the group consisting of halogen, hydroxy, amino,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, halo C₁-C₆alkyl,and halo C₁-C₆alkoxy.

In a twenty second embodiment, the disclosure provides compounds of thetwentieth or twenty-first embodiment in which the compound isrepresented by Formula VII:

Wherein R^(B) is H or methyl;

R⁴ and R⁶ are each independently hydrogen or methyl;

or R⁴ and R⁶, taken in combination form a fused cyclopropyl ring;

G is O, S, or N(H);

R¹⁶ is halogen, hydroxy, amino, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, halo C₁-C₆alkyl, and halo C₁-C₆alkoxy.

In a twenty third embodiment, the invention provides compounds of thefirst or second embodiment and pharmaceutically acceptable salts thereofin which the compound is recited in the below Table A.

Table A

-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(1H-pyrrol-1-yl)-1,3-benzothiazole-6-carboxamide;-   racemic-endo 2-methyl-2-propanyl    7-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate;-   racemic-endo 2-methyl-2-propanyl    6-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((4-cyclopropyl-2-pyrimidinyl)amino)-2,5-difluorobenzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((4-cyclopropyl-2-pyrimidinyl)amino)-2,3-difluorobenzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-phenyl-1H-indazole-6-carboxamide;-   2-methyl-2-propanyl    (4-(((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-methylphenyl)carbamate;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(2,2-dimethylpropanoyl)-2,3-dihydro-1H-indole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1,3-thiazol-4-yl)benzamide;-   4-benzamido-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)benzamide;-   N-(4-(((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)-2-pyridinecarboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(phenylethynyl)benzamide;-   6-(1H-benzimidazol-1-yl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-pyridinecarboxamide;-   4-((5-chloro-2-pyridinyl)oxy)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-fluorobenzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1,1-dioxido-1,2-thiazolidin-2-yl)benzamide;-   2-methyl-2-propanyl    (3-chloro-4-(((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)carbamate;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-4-(3-methylbutanamido)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4-methyl-1H-pyrazol-1-yl)benzamide;-   4-(1H-benzotriazol-1-yl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-<4-pyridinyl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-6-(cyclopropylmethoxy)-3-pyridinecarboxamide;-   4-(3-chloro-2-pyridinyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(3-pyridinyl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(3-methyl-1H-pyrazol-1-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4-methyl-1H-pyrazol-1-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-methyl-4-(4-methyl-1H-pyrazol-1-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-fluoro-4-(4-methyl-1H-pyrazol-1-yl)benzamide;-   racemic-endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-(4-fluorophenyl)-2-pyridinecarboxamide;-   racemic-endo    6-(4-chlorophenyl)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-pyridinecarboxamide;-   6-(4-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-pyridinecarboxamide;-   racemic-endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(3-methylanilino)-5-pyrimidinecarboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyridinyl)-6-fluoro-1H-indazole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyano-6-methyl-2-pyridinyl)-1H-indazole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-2-pyridinyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-5-carboxamide;-   Mixture of two diastereomers:    (S)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-methyl-2-pyridinyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide    and    (R)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-methyl-2-pyridinyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(4-methyl-2-pyrimidinyl)-1H-indole-6-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-6-methoxy-1-(4-methyl-2-pyrimidinyl)-1H-indole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-methyl-3-(6-methyl-2-pyridinyl)-1H-indazole-6-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-methyl-3-(6-(trifluoromethyl)-2-pyridinyl)-1H-indazole-6-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-methyl-3-phenyl-1H-indazole-6-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-<(3-fluorophenoxy)methyl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(2-thiophenylmethoxy)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((2-methylphenyl)sulfanyl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(3-methylbutoxy)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((2-cyanophenyl)sulfanyl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyridinyl)-3-methyl-1H-indazole-5-carboxamide;-   6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyridinyl)-1H-indazole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyridinyl)-6-methyl-1H-indazole-5-carboxamide;-   5-bromo-3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-methyl-1H-indole-2-carboxamide;-   Mixture of two diastereomers:    (2R)-5-bromo-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3-dihydro-1H-indene-2-carboxamide,    and    (2S)-5-bromo-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3-dihydro-1H-indene-2-carboxamide;-   5-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-benzothiophene-2-carboxamide;-   N-benzyl-3-bromo-N-(2-(((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)amino)-2-oxoethyl)benzamide;-   N-benzyl-3-chloro-N-(2-(((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)amino)-2-oxoethyl)benzamide;-   3-bromo-N-(2-(((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)amino)-2-oxoethyl)benzamide;-   3-chloro-N-(2-(((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)amino)-2-oxoethyl)benzamide;-   Mixture of two diastereomers:    (3R)-1-(3-chlorophenyl)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-oxo-3-pyrrolidinecarboxamide,    and    (3S)-1-(3-chlorophenyl)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-oxo-3-pyrrolidinecarboxamide;-   Mixture of two diastereomers:    (3R)-1-(3-bromophenyl)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-oxo-3-pyrrolidinecarboxamide,    and    (3S)-1-(3-bromophenyl)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-oxo-3-pyrrolidinecarboxamide;-   Mixture of two diastereomers:    (3R)-1-(3-chlorophenyl)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-3-pyrrolidinecarboxamide,    and    (3S)-1-(3-chlorophenyl)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-3-pyrrolidinecarboxamide;-   2-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1,3-thiazole-4-carboxamide;-   2-(4-chloro-3-(trifluoromethyl)phenoxy)-N-((endo)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide    enantiomer 1;-   2-(4-chloro-3-(trifluoromethyl)phenoxy)-N-((endo)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide    enantiomer 2;-   3-(3-chlorophenyl)-N-((endo)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1,2-oxazole-5-carboxamide    enantiomer 1;-   3-(3-chlorophenyl)-N-((endo)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1,2-oxazole-5-carboxamide    enantiomer 2;-   Racemic, endo    2-((4-chloro-3-(trifluoromethyl)phenyl)amino)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide;-   Racemic, endo    3-bromo-N-(1-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)amino)-1-oxopropan-2-yl)benzamide;-   Racemic, endo    3-bromo-N-(1-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)benzamide;-   (endo)-7-cyano-N-(4-(3-(trifluoromethyl)phenyl)-1,3-thiazol-2-yl)-7-azabicyclo[2.2.1]heptane-2-carboxamide;-   (endo)-7-cyano-N-(4-(3-(trifluoromethyl)phenyl)-1,3-thiazol-2-yl)-7-azabicyclo[2.2.1]heptane-2-carboxamide;-   (exo)-7-cyano-N-(4-(3-(trifluoromethyl)phenol)-1,3-thiazol-2-yl)-7-azabicyclo[2.2.1]heptane-2-carboxamide;-   (exo)-7-cyano-N-(4-(3-(trifluoromethyl)phenyl)-1,3-thiazol-2-yl)-7-azabicyclo[2.2.1]heptane-2-carboxamide;-   (endo)-2-((5-(2-fluoro-5-methylphenyl)-2,3-dihydro-1H-indol-1-yl)carbonyl)-7-azabicyclo[2.2.1]heptane-7-carbonitrile;-   (endo)-2-((5-(2-fluoro-5-methylphenyl)-2,3-dihydro-1H-indol-1-yl)carbonyl)-7-azabicyclo[2.2.1]heptane-7-carbonitrile;-   (exo)-2-((5-(2-fluoro-5-methylphenyl)-2,3-dihydro-1H-indol-1-yl)carbonyl)-7-azabicyclo[2.2.1]heptane-7-carbonitrile;-   (exo)-2-((5-(2-fluoro-5-methylphenyl)-2,3-dihydro-1H-indol-1-yl)carbonyl)-7-azabicyclo[2.2.1]heptane-7-carbonitrile;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4,6-dimethyl-2-pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyridinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyradinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3-cyclopropylphenyl)-2,3-dihydro-1H-indole-5-carboxamide;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyclopropyl-2-pyridinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methoxy-2-pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide:-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-(trifluoromethyl)-2-pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-(2-methyl-2-propanyl)-2-pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-(2-propanyl)-2-pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-ethyl-2-pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyano-2-pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyano-6-methyl-2-pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-(difluoromethyl)-2-pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-6-(trifluoromethyl)-2-pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3-fluoro-6-methyl-2-pyridinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-2-pyrimidinyl)-1H-indole-5-carboxamide;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(2-pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(5-methyl-2-pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyclopropyl-2-pyrimidinyl)-N-methyl-2,3-dihydro-1H-indole-5-carboxamide;-   N-((1S,2S,4R)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyclopropyl-2-pyrimidinyl)-N-methyl-2,3-dihydro-1H-indole-5-carboxamide    (peak 2 derived);-   Racemic, endo    N˜5˜-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N˜1˜-cyclopropyl-2,3-dihydro-1H-indole-1,5-dicarboxamide:-   Racemic, endo    1-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(4-(trifluoromethyl)phenyl)urea;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(cyclopropylmethoxy)-4-(1-methyl-1H-pyrazol-4-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-pyrazol-4-yl)-3-propoxybenzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-pyrazol-4-yl)-3-(2-propanyloxy)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-methoxy-4-(1-methy    1-1H-pyrazol-4-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-pyrazol-4-yl)-3-(trifluoromethoxy)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(6-(trifluoromethyl)-2-pyridinyl)-1H-indazole-6-carboxamide;-   Racemic, endo    2-((3-bromobenzyl)(methyl)amino)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide,-   Racemic, endo    2-(4-chloro-2-cyclohexylphenoxy)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide;-   N˜2˜-benzyl-N˜2˜-(3-bromobenzyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)glycinamide;-   N˜2˜-benzyl-N˜2˜-(3-chlorobenzyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)glycinamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-<5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-ylsulfanyl)acetamide;-   N˜2˜-(3-bromobenzyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N˜2˜-(2-methylpropyl)glycinamide;-   N˜2˜-(3-chlorobenzyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N˜2˜-(4-methoxybenzyl)glycinamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(5,7-dichloro-3,4-dihydro-2(1H)-isoquinolinyl)acetamide;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(2,4-dichloro-5-ethyl-3-methylphenoxy)acetamide;-   Racemic, endo    2-((5-chlorobenzo[d]thiazol-2-yl)thio)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide;-   Racemic, endo    2-(4-((4-chlorophenyl)thio)piperidine-1-carbonyl)-7-azabicyclo[2.2.1]heptane-7-carbonitrile;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-2-pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(cyclopropylcarbonyl)-2,3-dihydro-1H-indole-5-carboxamide;-   6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-methyl-2-pyridinyl)-1H-indazole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-methyl-2-pyridinyl)-1H-indazole-S-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-6-fluoro-1-(6-methyl-2-pyridinyl)-1H-indazole-5-carboxamide;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4-cyclopropyl-2-pyrimidinyl)-3,4-dihydro-2H-1,4-benzoxazine-7-carboxamide;-   2-((4-chloro-1-naphthalenyl)oxy)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide;-   2-((4-chloro-1-naphthalenyl)oxy)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide    (peak 2 derived);-   Racemic, endo 2-methyl-2-propanyl    5-((7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)-2,3-dihydro-1H-indole-1-carboxylate;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-2-pyrimidinyl)-1H-indazole-5-carboxamide;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-2-pyrimidinyl)-1H-benzimidazole-5-carboxamide;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyclopropyl-2-pyridinyl)-1H-indazole-5-carboxamide;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyridinyl)-1H-indazole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyridinyl)-1H-indazole-5-carboxamide;-   3-(4-chloro-3-(trifluoromethyl)phenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)propanamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-ethyl-2-pyridinyl)-1H-indazole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-2-pyrimidinyl)-1H-pyrrolo[3,2-b]pyridine-S-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-fluoro-1-(4-methyl-2-pyrimidinyl)-1H-indole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(methyl(4-methyl-2-pyrimidinyl)amino)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-methyl-1-(4-methyl-2-pyrimidinyl)-1H-indole-5-carboxamide;-   Racemic, endo    N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-<2-pyrimidinylamino)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-6-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-indole-2-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyclopropyl-2-pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyclopropyl-2-pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-pyrazol-4-yl)benzamide;-   6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-2-pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide;-   5-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-methyl-1,3-thiazole-2-carboxamide;    and-   5-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1,3-thiazole-2-carboxamide.

In a twenty fourth embodiment, the invention provides compounds of thefirst embodiment and pharmaceutically acceptable salts thereof in whichthe compound is recited in the below Table B.

Table B

-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((cyclopropylcarbonyl)amino)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1H-indazol-1-yl)benzamide,-   (3R)-6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide;-   (3S)-6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide.-   (4R)-7-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3,4,5-tetrahydro-1-benzoxepine-4-carboxamide;-   5-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-methyl-3-(6-methyl-2-pyridinyl)-1H-indazole-6-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(cyclopropylmethyl)-3-(6-methyl-2-pyridinyl)-1H-indazole-6-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(2-methylpropyl)-3-(6-methyl-2-pyridinyl)-1H-indazole-6-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-<6-methyl-2-pyridinyl)-1-(4,4,4-trifluorobutyl)-1H-indazole-6-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(6-methyl-2-pyridinyl)-1-propyl-1H-indazole-6-carboxamide;-   6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(2,2,2-trifluoroethoxy)-2-pyridinyl)-1H-indazole-5-carboxamide;-   6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(1,7-naphthyridin-2-yl)-1H-indazole-5-carboxamide;-   6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(cyanomethyl)-2-pyridinyl)-1H-indazole-5-carboxamide;-   6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(1,8-naphthyridin-2-yl)-1H-indazole-5-carboxamide;-   4-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1,3-thiazole-2-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(3-thiophenyl)-1,3-thiazole-4-carboxamide;-   1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1H-pyrazole-3-carboxamide;-   1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-methyl-1H-pyrazole-3-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-<2-methyl-1,3-thiazol-4-yl)benzamide,-   7-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-phenyl-3-pyrrolidinecarboxamide;-   (2S,3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-methyl-1-phenyl-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyano-2-fluorophenyl)-3-pyrrolidinecarboxamide;-   (3S)-1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-pyrrolidinecarboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-phenyl-2-furancarboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-(3-(2-propanyl)phenyl)-2-furancarboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-(3-(trifluoromethyl)phenyl)-2-furancarboxamide;-   (3R)-1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-piperidinecarboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-(trifluoromethyl)-2-pyrimidinyl)-4-piperidinecarboxamide;-   (3S)-1-(3-bromophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-pyrrolidinecarboxamide;-   (3S)-1-(3-chloro-4-(trifluoromethyl)phenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-pyrrolidinecarboxamide;-   (3S)-6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3,4-dihydro-2H-chromene-3-carboxamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-cyclopropyl-2-pyridinyl)benzamide:-   1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-piperidinecarboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-4-piperidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-<4-methyl-2-pyridinyl)-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(5-cyano-3-pyridinyl)-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(2-methoxy-4-pyridinyl)-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-methy)-2-pyridinyl)-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-methyl-2-pyrazinyl)-3-pyrrolidinecarboxamide;-   (3R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-3-methyl-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-3-fluoro-3-pyrrolidinecarboxamide;-   (1S,4R,5R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(3,5-dichlorophenyl)-2-azabicyclo[3.1.0]hexane-4-carboxamide;-   2-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1,3-oxazole-5-carboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3-(cyanomethyl)phenyl)-3-pyrrolidinecarboxamide;-   (3S)-1-(3-chloro-5-methoxyphenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-pyrrolidinecarboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-L-prolinamide;-   3′-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)[biphenyl]-3-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(2,5-dichlorophenyl)-5-methyl-2-pyridinecarboxamide;-   4-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-methyl-2-pyridinecarboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(1-cyanocyclopropyl)-2-pyridinyl)-4-piperidinecarboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-6-(3-(1-cyanocyclopropyl)phenyl)-3-pyridinecarboxamide;-   3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-cyclopropyl-5′-fluoro[biphenyl]-4-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-6-(1-cyanocyclopropyl)[2,3′-bipyridine]-6′-carboxamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1-ethynylcyclopropyl)-2-pyridinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3R)-3-cyano-3-methyl-2,3-dihydro-1H-inden-5-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3S)-3-cyano-3-methyl-2,3-dihydro-1H-inden-5-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(2-methyl-2-propanyl)-2-pyridinyl)benzamide,-   (1S,6R,7R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(3,5-dichlorophenyl)-3-azabicyclo[4.1.0]heptane-7-carboxamide;-   (1R,6S,7R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(3,5-dichlorophenyl)-3-azabicyclo[4.1.0]heptane-7-carboxamide;-   (1S,6R,7R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(3,5-dichlorophenyl)-3-azabicyclo[4.1.0]heptane-7-carboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyridinyl)-3-piperidinecarboxamide;-   (1    S,5S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(3,5-dichlorophenyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide:-   (1R,5R)-N-((1R,2S,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(3,5-dichlorophenyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide;-   (1R,5S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(3,5-dichlorophenyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(1-cyanocyclopropyl)-2-pyridinyl)-3-piperidinecarboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-cyclopentyl-1H-indazole-3-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyridinyl)-4-piperidinecarboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3-carboxamide,-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(2-cyano-2-propanyl)-2-pyrazinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3S)-3-cyano-1-piperidinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3R)-3-cyano-1-piperidinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3S)-3-cyano-1-piperidinyl)benzamide:-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3R)-3-cyano-3-methyl-2,3-dihydro-1H-inden-5-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((1    S,2S,5R)-2-cyano-6-azabicyclo[3.2.1]octan-6-yl)benzamide,-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3-cyanophenyl)-1H-pyrazole-3-carboxamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1-cyanocyclobutyl)-2-pyridinyl)benzamide,-   (2S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorobenzyl)-2-azetidinecarboxamide;-   (2R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorobenzyl)-2-azetidinecarboxamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3S)-3-(cyanomethyl)-1-pyrrolidinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3R)-3-(cyanomethyl)-1-pyrrolidinyl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3-cyanophenyl)-1H-indazole-3-carboxamide;-   (3R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorobenzyl)-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(1-cyanocyclopropyl)-2-pyridinyl)-3-pyrrolidinecarboxamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((1S,2R,5R)-2-cyano-6-azabicyclo[3.2.1]octan-6-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((1-cyanocyclopropyl)methoxy)benzamide,-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1-cyanocyclopropyl)-2-pyridinyl)-2-cyclopropylbenzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-((cis-3-cyanocyclobutyl)oxy)benzamide;-   2-chloro-N-((1S,2R,4R)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3R)-3-(cyanomethyl)-1-pyrrolidinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((cis-3-cyanocyclobutyl)oxy)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1-cyano-3,3-difluorocyclobutyl)-3-pyridinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-(1-cyanocyclopropyl)[biphenyl]-3-carboxamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3S)-3-(cyanomethyl)-1-piperidinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3R)-3-(cyanomethyl)-1-piperidinyl)benzamide;-   3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-(1-cyanocyclopropyl)-5′-fluoro[biphenyl]-4-carboxamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(5,6-dihydrocyclopenta[c]pyrazol-1    (4H)-yl)benzamide:-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3S)-3-(cyanomethyl)-1-piperidinyl)benzamide;-   (3S)-6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N,9-dimethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyridinyl)-6-fluoro-N-methyl-1H-indazole-5-carboxamide,-   6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N-methyl-1-(6-methyl-2-pyridinyl)-1H-indazole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-6-fluoro-N-methyl-1-(6-methyl-2-pyridinyl)-1H-indazole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N,1-dimethyl-3-(6-methyl-2-pyridinyl)-1H-indazole-6-carboxamide;-   (3R)-1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N-methyl-3-pyrrolidinecarboxamide;-   (3S)-1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N-methyl-3-pyrrolidinecarboxamide;-   (3R)-1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N-methyl-5-oxo-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-N-methyl-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3-cyano-6-(trifluoromethyl)-2-pyridinyl)-N-methyl-3-pyrrolidinecarboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N-methyl-1-(2,3,5-trichlorophenyl)-L-prolinamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N-methyl-1-(2,3,5-trichlorophenyl)-D-prolinamide:-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-6-(4-methyl-2-pyrimidinyl)-1H-indole-2-carboxamide;-   5-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-furancarboxamide.-   (3R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyclopropyl)-2-pyrimidinyl)-3-pyrrolidinecarboxamide;-   (3R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3-(trifluoromethyl)phenyl)-3-pyrrolidinecarboxamide;-   (3R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-3-pyrrolidinecarboxamide;-   (3R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(trifluoromethyl)-2-pyridinyl)-3-pyrrolidinecarboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(2-quinolinyl)-1H-indazole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-<6-(1H-imidazol-1-yl)-2-pyridinyl)-1H-indazole-5-carboxamide:-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-phenyl-2-pyridinyl)-1H-indazole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-<6-(1H-pyrazol-1-yl)-2-pyridinyl)-1H-indazole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(1,1-difluoroethyl)-2-pyridinyl)-1H-indazole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-<difluoromethoxy)-2-pyridinyl)-1H-indazole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(difluoromethyl)-2-pyridinyl)-1H-indazole-5-carboxamide;-   1-([2,2′-bipyridin]-6-yl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1H-indazole-5-carboxamide;-   (1R,5R)-3-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-azabicyclo[3.1.0]hexane-1-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-1H-pyrazole-3-carboxamide;-   (1S,4R,5S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(3,5-dichlorophenyl)-2-azabicyclo[3.1.0]hexane-4-carboxamide;-   (1S,4S,5S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(3,5-dichlorophenyl)-2-azabicyclo[3.1.0]hexane-4-carboxamide;-   (1S,4S,5S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(3,5-dichlorophenyl)-2-azabicyclo[3,1,0]hexane-4-carboxamide;-   (4S)-N-((1    S,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-4-azepanecarboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1,3-thiazole-2-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(3-cyanophenyl)-1,3-thiazole-4-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(3-cyclopropylphenyl)-1,3-thiazole-4-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-7-(4-methyl-2-pyrimidinyl)-1H-indole-3-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-7-(6-methyl-2-pyridinyl)-1H-indole-3-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-methyl-2-pyridinyl)-7-(trifluoromethyl)-1H-indazole-5-carboxamide;-   (3R)-1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-oxo-3-pyrrolidinecarboxamide;-   (3S)-1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-oxo-3-pyrrolidinecarboxamide;-   (3S)-1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-pyrrolidinecarboxamide;-   (3R)-1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-pyrrolidinecarboxamide;-   (2S)-5-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3-dihydro-1H-indene-2-carboxamide;-   (2R)-5-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3-dihydro-1H-indene-2-carboxamide,-   (3R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyclopropyl-2-pyrimidinyl)-3-pyrrolidinecarboxamide;-   (3R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(trifluoromethyl)-2-pyridinyl)-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(trifluoromethyl)-2-pyridinyl)-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-3-pyrrolidinecarboxamide;-   (3S)-1-(5-chloro-2-cyanophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyano-4-(trifluoromethyl)-2-pyridinyl)-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyano-4-methyl-2-pyridinyl)-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-6-(trifluoromethyl)-2-pyridinyl)-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyano-6-(trifluoromethyl)-2-pyridinyl)-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3-cyano-6-(trifluoromethyl)-2-pyridinyl)-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(trifluoromethyl)-2-pyrazinyl)-3-pyrrolidinecarboxamide;-   (3S)-1-(3-chloro-6-(trifluoromethyl)-2-pyridinyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3-methylpheny))-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3-methoxyphenyl)-3-pyrrolidinecarboxamide;-   7-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3-dihydro-1-benzoxepine-4-carboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(2,5-dichlorophenyl)-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichloro-4-(trifluoromethoxy)phenyl)-3-pyrrolidinecarboxamide;-   (3S)-1-(3-chloro-5-(trifluoromethyl)phenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-pyrrolidinecarboxamide;-   (3S)-1-(3-chloro)-5-methylphenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-pyrrolidinecarboxamide;-   (3S)-1-(5-chloro-2-methylphenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-pyrrolidinecarboxamide;-   6-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-pyridinecarboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(2,5-dichlorophenyl)-2-pyridinecarboxamide:-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(3,5-dichlorophenyl)-2-pyridinecarboxamide;-   4-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-pyridinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichloro-4-methoxyphenyl)-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichloro-4-fluorophenyl)-3-pyrrolidinecarboxamide,-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3-cyclopropylphenyl)-3-pyrrolidinecarboxamide;-   (2S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(3,5-dichlorophenyl)-2-morpholinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-<2,3,5-trichlorophenyl)-3-pyrrolidinecarboxamide.-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-1H-pyrazole-4-carboxamide;-   3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-1H-pyrazole-4-carboxamide;-   (3S)-1-(3-chloro-5-cyanophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-pyrrolidinecarboxamide;-   (3S)-1-(2-chloro-5-cyanophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(2-oxo-1-(2-propanyl)-5-(trifluoromethyl)-1,2-dihydro-3-pyridinyl)-3-pyrrolidinecarboxamide,-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,4-dichlorophenyl)-3-pyrrolidinecarboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(2,3-dichlorophenyl)-3-pyrrolidinecarboxamide.-   (3S)-1-(2-chloro-5-(trifluoromethyl)phenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-pyrrolidinecarboxamide;-   (1R,4R,5R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(3,5-dichlorophenyl)-2-azabicyclo[3,1,0]hexane-4-carboxamide;-   (1    S,3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2,5-dichlorophenyl)cyclopentanecarboxamide;-   (1R,3R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2,5-dichlorophenyl)cyclopentanecarboxamide:-   (1S,3R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2,5-dichlorophenyl)cyclopentanecarboxamide:-   (5R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(1,1-difluoroethyl)-2-pyridinyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide;-   (5R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-<difluoromethoxy)-2-pyridinyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide;-   (5S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(6-(1-cyanocyclopropyl)-2-pyridinyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;-   (5S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(6-(1,1-difluoroethyl)-2-pyridinyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;-   (5S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(6-(difluoromethoxy)-2-pyridinyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;-   (5R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(6-(1,1-difluoroethyl)-2-pyridinyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide:-   (5R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-<6-(difluoromethoxy)-2-pyridinyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;-   (5R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(6-(difluoromethyl)-2-pyridinyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;-   (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-3-azepanecarboxamide;-   7-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxamide;-   7-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1,2,3,5-tetrahydro-4H-1,4-benzodiazepine-4-carboxamide;-   1-(6-acetamido-2-pyridinyl)-6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1H-indazole-5-carboxamide;-   (5R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-methyl-2-pyridinyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide;-   (5S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-methyl-2-pyridinyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide;-   (5R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(6-methyl-2-pyridinyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;-   (5S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(6-methyl-2-pyridinyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;-   (5S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(6-cyclopropyl-2-pyridinyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide:-   (5R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(6-cyclopropyl-2-pyridinyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide;-   6-(5-azaspiro[2.5]octan-5-yl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-pyrimidinecarboxamide;-   (2S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(2,3-dichlorophenyl)-1-pyrrolidinecarboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-6-((2R)-2-methyl-2-phenyl-4-morpholinyl)-4-pyrimidinecarboxamide;-   6-((2R)-2-(4-chlorophenyl)-2-methyl-4-morpholinyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-pyrimidinecarboxamide;-   6-(((1-(4-bromophenyl)cyclopropyl)methyl)(methyl)amino)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-pyrimidinecarboxamide:-   2-chloro-N-((1S,2R,5S)-8-cyano-8-azabicyclo[3.2.1]octan-2-yl)-4-(4-methyl-1H-pyrazol-1-yl)benzamide;-   3-(6-chloro-2,3-dihydro-1H-indol-1-yl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)propanamide;-   (2S)-2-(3-bromo-2-methylphenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-pyrrolidinecarboxamide;-   (2S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(2,3-dichlorophenyl)-1-azetidinecarboxamide:-   1-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(((1    S,3S)-3-(2-propanyl)-2,3-dihydro-1H-inden-1-yl)methyl)urea;-   1-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-((1R)-1-(2,3-dichlorophenyl)ethyl)urea:-   (2E)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(2,5-dichlorophenyl)-2-methyl-2-butenamide:-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(2,5-dichlorophenyl)butanamide;-   (1R,3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2,5-dichlorophenyl)cyclopentanecarboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(4-fluorophenoxy)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(4-fluorobenzyl)benzamide;-   3-(4-chlorophenoxy)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)benzamide;-   (1    S,2S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(2,5-dichlorobenzyl)cyclopropanecarboxamide;-   1-(((1R)-7-chloro-1,2,3,4-tetrahydro-1-naphthalenyl)methyl)-3-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)urea:-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(4-cyanophenoxy)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)dibenzo[b,d]furan-3-carboxamide;-   (2E)-3-(5-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-propenamide;-   2-(3-bromo-2-cyanophenoxy)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide;-   N-(2-(((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)amino)-2-oxoethyl)-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide;-   (2S,3E)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(2,5-dichlorophenyl)-2-methoxy-3-butenamide;-   (3E)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(2,5-dichlorophenyl)-N-methyl-3-butenamide;-   2′,5′-dichloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)[biphenyl]-3-carboxamide;-   (3E)-4-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-butenamide;-   (2E)-3-(5-chloro-1-ethyl-1H-indol-3-yl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-methyl-2-propenamide;-   (3E)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(2,5-dichlorophenyl)-3-butenamide:-   1-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2-(2,5-dichlorophenyl)ethyl)-1,3-dimethylurea;-   (3R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide;-   1-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2-(2,5-dichlorophenyl)ethyl)urea;-   (2E)-3-(5-chloro)-1-benzothiophen-3-yl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-methyl-2-propenamide;-   3′-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)[biphenyl]-3-carboxamide,-   (2E)-3-(5-chloro-1H-indazol-3-yl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-methyl)-2-propenamide;-   1-(2-(2-bromo-5-chlorophenyl)ethyl)-3-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1,3-dimethylurea;-   N′-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N-(2-hydroxyethyl)-N-((1R,3R,5S,7r)-tricyclo[3.3.1.1˜3,7˜]decan-1-ylmethyl)ethanediamide;-   7-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxamide;-   8-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxamide,-   2′,3-dichloro-N-((l    R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-(cyanomethyl)[biphenyl]-4-carboxamide:-   3,3′-dichloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5′-(cyanomethyl)[biphenyl]-4-carboxamide;-   2′,3-dichloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5′-(cyanomethyl)[biphenyl]-4-carboxamide;-   3,4′-dichloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-(cyanomethyl)[biphenyl]-4-carboxamide;-   3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-(2-cyano-2-propanyl)[biphenyl]-4-carboxamide;-   3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-(cyanomethyl)-5′-fluoro[biphenyl]-4-carboxamide;-   3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-(cyanomethyl)-4′-fluoro[biphenyl]-4-carboxamide,-   3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-(cyanomethyl)-2′-fluoro[biphenyl]-4-carboxamide;-   3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5′-(cyanomethyl)-2′-fluoro[biphenyl]-4-carboxamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(2-cyano-2-propanyl)-2-pyridinyl)benzamide;-   3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5′-(cyanomethyl)-2′-methyl[biphenyl]-4-carboxamide;-   3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-(cyanomethyl)-4′-methyl[biphenyl]-4-carboxamide;-   3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-(cyanomethyl)-5′-methyl[biphenyl]-4-carboxamide;-   3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-(cyanomethyl)[biphenyl]-4-carboxamide;-   3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-(1-cyanocyclobutyl)[biphenyl]-4-carboxamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(methoxymethyl)-2-pyridinyl)benzamide,-   3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4′-(cyanomethyl)[biphenyl]-4-carboxamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1-cyanocyclopropyl)-2-pyridinyl)-N-methylbenzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(5-(1-cyanocyclopropyl)-3-pyridinyl)benzamide;-   4-(6-(acetyl(methyl)amino)-2-pyridinyl)-2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)benzamide:-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(5-(cyanomethyl)-3-pyridinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4-(cyanomethyl)-2-pyridinyl)benzamide,-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1-cyanocyclopropyl)-2-pyridinyl)-2-methylbenzamide;-   3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-(1-cyanocyclopropyl)[biphenyl]-4-carboxamide,-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(2-(cyanomethyl)-3-pyridinyl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1-cyanocyclopropyl)-2-pyridinyl)-2-(trifluoromethyl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1-cyanocyclopropyl)-2-pyridinyl)-2-fluorobenzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(imidazo[1,5-a]pyridin-6-yl)-2-(trifluoromethyl)benzamide:-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-fluoro-4-(1-methyl-1H-pyrazol-3-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-fluoro-4-(imidazo[1,5-a]pyridin-6-yl)benzamide;-   2,6-dichloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)benzamide;-   2,6-dichloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(imidazo[1,5-a]pyridin-6-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(5-cyano-2-pyrimidinyl)benzamide:-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4-cyano-2-pyrimidinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-methyl-2-pyrazinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(5-methyl-2-pyrazinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4-cyano-2-pyridinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-methyl-2-pyridinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(2-methyl-4-pyrimidinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-methyl-3-pyridazinyl)benzamide:-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(difluoromethyl)-2-pyridinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(cyanomethyl)-2-pyridinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(difluoromethoxy)-2-pyridinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1,1-difluoroethyl)-2-pyridinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-cyclopropyl-2-pyrazinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-cyano-2-pyridinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1-cyanocyclopropyl)-2-pyridinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(2,2,2-trifluoroethoxy)-2-pyridinyl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4-(cyanomethyl)-1H-pyrazol-1-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4-ethyl-1H-pyrazol-1-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(imidazo[1,2-a]pyridin-6-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-indazol-7-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(7-methylimidazo[1,2-a]pyridin-6-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(2-methylimidazo[1,2-a]pyridin-6-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(imidazo[1,2-a]pyridin-7-yl)benzamide:-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(imidazo[1,5-a]pyridin-6-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-pyrazol-3-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-pyrazol-5-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-cyclopropyl-1H-pyrazol-4-yl)benzamide:-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-(cyanomethyl)-1H-pyrazol-4-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-imidazol-4-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-pyrazol-4-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-<2-methylpropoxy)-4-(3-methyl-1H-pyrazol-1-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4-cyano-2-pyridinyl)-3-(2-methylpropoxy)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(5-methyl-2-pyrazinyl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-<2-methylpropoxy)-4-(6-methyl-2-pyridinyl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(4-methyl-2-pyrimidinyl)benzamide:-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(cyanomethyl)-2-pyridinyl)-3-(2-methylpropoxy)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(1-methyl-1H-pyrazol-3-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-<1-methyl-1H-pyrazol-5-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-imidazol-4-yl)-3-(2-methylpropoxy)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-cyano-2-pyridinyl)-3-(2-methylpropoxy)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(6-methyl-3-pyridazinyl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(2-methyl-4-pyrimidinyl)benzamide:-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-((2R)-2-methylbutoxy)-4-(1-methyl-1H-pyrazol-4-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-ethyl-1H-pyrazol-4-yl)-3-(2-methylpropoxy)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-cyclopropyl-1H-pyrazol-4-yl)-3-(2-methylpropoxy)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-methyl-4-(1-methyl-1H-pyrazol-4-yl)-1,3-benzothiazole-7-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-(2-methylpropoxy)-2,4-bis(1-methyl-1H-pyrazol-4-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-(2-methylpropoxy)-4-(1-methyl-1H-pyrazol-4-yl)benzamide,-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(1-methyl-1H-pyrazol-4-yl)benzamide;-   2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(4-methyl-1H-pyrazol-1-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-<2-methylpropoxy)-4-(4-methyl-1H-pyrazol-1-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-7-methyl-1-(6-methyl-2-pyridinyl)-1H-indazole-5-carboxamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N-methyl-3-(2-methylpropoxy)-4-(1-methyl-1H-pyrazol-4-yl)benzamide;-   3-butoxy-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-pyrazol-4-yl)benzamide:-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(cyclobutylmethoxy)-4-(1-methyl-1H-pyrazol-4-yl)benzamide;-   N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(1-methyl-1H-pyrazol-4-yl)benzamide,-   6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyano-2-pyridinyl)-1H-indazole-5-carboxamide;    and-   6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyano-2-pyridinyl)-1H-indazole-5-carboxamide.

In another embodiment synthetic intermediates are provided, whichintermediates are useful for the preparation of compounds of Formula (I)and subformulae thereof. Preferred synthetic intermediates provided inthe specification include racemates and enantiomerically enriched formsof compounds selected from:

and salts thereof. Wherein each of the above compounds may be racemic, amixture of diastereomers or enantiomerically enriched in a singlestereoisomer. The synthetic intermediates provided may be prepared incither endo or exo relative orientation. In certain aspects, the endogeometry is preferred for preparation of compounds provided by thedisclosure. Synthetic intermediates may be prepared in free base/acidform or as an acid or base addition salt. In certain embodimentshydrochloride salts are provided for primary amine syntheticintermediates.

Certain preferred synthetic intermediates provided by the disclosureinclude endo azanorbornane cores selected from:

each of which may be a free base or an acid addition salt (such as ahydrochloride salt, an trifluoroacetic acid salt or the like).

Certain preferred synthetic intermediates provided by the disclosureinclude endo azanorbornane cores selected from:

In another embodiment, pharmaceutical compositions are provided whichcomprise one or more pharmaceutically acceptable carriers and atherapeutically effective amount of a compound of any one of formulae Ior a subformulae thereof. In some aspects, the composition is formulatedin a form selected from the group consisting of an injectable fluid, anaerosol, a tablet a pill, a capsule, a syrup, a cream, a gel and atransdermal patch.

In another embodiment, combinations, in particular pharmaceuticalcombinations, are provided which comprise a therapeutically effectiveamount of the compound any one of formulae I or a subformulae thereof.

In another embodiment, methods of modulating USP30 protein activity in asubject are provided which comprise administering to the subject atherapeutically effective amount of Formula I or a subformulae thereof.In preferred aspects of the embodiment, methods of inhibiting USP30activity in a subject are provided, which comprise administering to thesubject a therapeutically effective amount of a compound of Formula I orsubformulae thereof. In certain aspects of the embodiment, method ofinhibiting USP30 activity in a subject are provided, which compriseadministering to the subject a therapeutically effective amount of acompound of Formula I or subformulae thereof.

In yet other embodiments, methods of treating a disorder or a disease ina subject mediated by USP30 protein activity are provided, in particularmethods of treating a disease or disorder mediated by USP30 proteinactivity are provided. The methods comprise administering to the subjecta therapeutically effective amount of the compound of Formula I or asubformulae thereof.

In another embodiment, methods of treating or preventing a disease ordisorder are provided where the disease or disorder is mediated bymitochondrial dysfunction. In certain aspects of the embodiment thedisease or disorder is selected from neurodegenerative diseases, cancer,diabetes, metabolic disorders, cardiovascular disease, psychiatricdisease and osteoarthritis. In certain specific aspects of theembodiment, the disease or disorder is selected from the groupconsisting of CNS disorder, neurodegenerative disease, multiplesclerosis, mitochondrial myopathy, encephalopathy, lactic acidosis,stroke-like episodes. Leber's hereditary optic neuropathy, cancer,neuropathy, ataxia, retinitis pigmentosa, maternally inherited Leighsyndrome. Danon disease, diabetes, diabetic nephropathy, metabolicdisorders, heart failure, ischemic heart disease leading to myocardialinfarction, psychiatric disease, schizophrenia, multiple sulfatasedeficiency, mucolipidosis II, mucolipidosis III, mucolipidosis IV,GMI-gangliosidosis, neuronal ceroid-lipofuscinoses, Alpers disease,Barth syndrome, Beta-oxidation defects, carnitine-acyl-carnitinedeficiency, carnitine deficiency, creatine deficiency syndromes,co-enzyme Q10 deficiency, complex I deficiency, complex II deficiency,complex III deficiency, complex IV deficiency, complex V deficiency, COXdeficiency, chronic progressive external ophthalmoplegia syndrome, CPT Ideficiency, CPT II deficiency, glutaric aciduria type II, Kearns-Sayresyndrome, lactic acidosis, long-chain acyl-CoA dehydrogenase deficiency.Leigh disease or syndrome, lethal infantile cardiomyopathy, Luftdisease, glutaric aciduria type II, medium-chain acyl-CoA dehydrogenasedeficiency, myoclonic epilepsy and ragged-red fiber syndrome,mitochondrial cytopathy, mitochondrial recessive ataxia syndrome,mitochondrial DNA depiction syndrome, myoneurogastointestinal disorderand encephalopathy, Stiff Person syndrome, pyruvate dehydrogenasedeficiency, pyruvate carboxylase deficiency. POLG mutations,medium/short-chain 3-hydroxy acyl-CoA dehydrogenase deficiency, verylong-chain acyl-CoA dehydrogenase deficiency, and age-dependent declinein cognitive function and muscle strength which method comprises thestep of administering to a subject in need of therapy a therapeuticallyeffective amount of a compound or salt of Formula I or a subformulaethereof. In certain aspects of this embodiment, the method comprisestreating a disease or disorder selected from Parkinson's disease,Alzheimer's disease, amyotrophic lateral sclerosis. Huntington'sdisease, ischemia, stroke, dementia with Lewy bodies, frontotemporaldementia, autosomal recessive juvenile Parkinson's disease where parkinis mutated and Parkinson's disease related to mutations in α-synuclein,parkin and PINK1. In certain instances, the treatment methods and/or theprevention methods are suitable for the treatment and or prevention ofParkinson's Disease.

In another aspect, the invention provides for the use of compounds ofFormula I or a subformulae thereof for use in the preparation of amedicament or for use in the manufacture of a medicament for thetreatment of a disorder or disease in a subject mediated by USP30activity. In certain other aspects, the invention provides for the useof a compound according to formula I or a subformulae thereof in thetreatment of a disease or disorder mediated by mitochondrialdysfunction. In certain uses of the embodiment, the disease or disorderis selected from neurodegenerative diseases, cancer, diabetes, metabolicdisorders, cardiovascular disease, psychiatric disease andosteoarthritis. More particularly, the use of compounds of Formula I inthe preparation of a medicament or in use in the manufacture of amedicament for treatment of a disease or disorder selected from CNSdisorder, neurodegenerative disease, multiple sclerosis, mitochondrialmyopathy, encephalopathy, lactic acidosis, stroke-like episodes, Leber'shereditary optic neuropathy, cancer, neuropathy, ataxia, retinitispigmentosa, maternally inherited Leigh syndrome, Danon disease,diabetes, diabetic nephropathy, metabolic disorders, heart failure,ischemic heart disease leading to myocardial infarction, psychiatricdisease, schizophrenia, multiple sulfatase deficiency, mucolipidosis II,mucolipidosis III, mucolipidosis IV, GMI-gangliosidosis, neuronalceroid-lipofuscinoses, Alpers disease, Barth syndrome, Beta-oxidationdefects, carnitine-acyl-carnitine deficiency, carnitine deficiency,creatine deficiency syndromes, co-enzyme Q10 deficiency, complex Ideficiency, complex II deficiency, complex III deficiency, complex IVdeficiency, complex V deficiency, COX deficiency, chronic progressiveexternal ophthalmoplegia syndrome, CPT I deficiency, CPT II deficiency,glutaric aciduria type II, Kearns-Sayre syndrome, lactic acidosis,long-chain acyl-CoA dehydrogenase deficiency, Leigh disease or syndrome,lethal infantile cardiomyopathy. Luft disease, glutaric aciduria type ILmedium-chain acyl-CoA dehydrogenase deficiency, myoclonic epilepsy andragged-red fiber syndrome, mitochondrial cytopathy, mitochondrialrecessive ataxia syndrome, mitochondrial DNA depiction syndrome,myoneurogastointestinal disorder and encephalopathy, Stiff Personsyndrome, pyruvate dehydrogenase deficiency, pyruvate carboxylasedeficiency. POLG mutations, medium/short-chain 3-hydroxyacyl-CoAdehydrogenase deficiency, very long-chain acyl-CoA dehydrogenasedeficiency, and age-dependent decline in cognitive function and musclestrength. In certain instances, the invention provides for the use ofcompounds of Formula I or a subformulae thereof for use in thepreparation of a medicament or for use in the manufacture of amedicament or the treatment of a disease or disorder in a subjectselected from Parkinson's disease, Alzheimer's disease, amyotrophiclateral sclerosis, Huntington's disease, ischemia, stroke, dementia withLewy bodies, frontotemporal dementia, autosomal recessive juvenileParkinson's disease where parkin is mutated and Parkinson's diseaserelated to mutations in α-synuclein, parkin and PINK1. In certaininstances, the invention provides for the use of compounds of Formula Ior a subformulae thereof for use in the preparation of a medicament orfor use in the manufacture of a medicament or the treatment ofParkinson's disease.

For purposes of interpreting this specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa.

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched hydrocarbon moiety having up to 20 carbon atoms. Unlessotherwise provided, alkyl refers to hydrocarbon moieties having 1 to 20carbon atoms, 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbonatoms, or 1 to 4 carbon atoms. Representative examples of alkyl include,but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl,n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

As used herein, the term “alkylene” refers to divalent alkyl group asdefined herein above having 1 to 20 carbon atoms. Unless otherwiseprovided, alkylene refers to moieties having 1 to 20 carbon atoms, 1 to16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4carbon atoms. Representative examples of alkylene include, but are notlimited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene,sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene,neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene,2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene, n-decyleneand the like.

As used herein, the term “haloalkyl” refers to an alkyl as definedherein, which is substituted with one or more halo groups as definedherein. The haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkylincluding perhaloalkyl. A monohaloalkyl can have one iodo, bromo, chloroor fluoro within the alkyl group. Dihaloalkyl and polyhaloalkyl groupscan have two or more of the same halo atoms or a combination ofdifferent halo groups within the alkyl. Typically the polyhaloalkylcontains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups.Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl,trifluoromethyl, chloro methyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. A perhaloalkyl refers to an alkyl having all hydrogenatoms replaced with halo atoms.

As used herein, the term “hydroxy alkyl” refers to an alkyl as definedherein which is substituted with one or more hydroxy groups. The term“hydroxy cycloalkyl-alkyl” refers to an alkyl group that is substitutedwith a cycloalkyl group, as defined herein, and further substituted witha hydroxy group. The hydroxy group can be on the alkyl group, thecycloalkyl group, or on each of the alkyl and cycloalkyl groups.

The term “aryl” refers to an aromatic hydrocarbon group having 6-20carbon atoms in the ring portion. Typically, aryl is monocyclic,bicyclic or tricyclic aryl having 6-20 carbon atoms. Furthermore, theterm “aryl” as used herein, refers to an aromatic substituent which canbe a single aromatic ring, or multiple aromatic rings that are fusedtogether. Non-limiting examples include phenyl, naphthyl ortetrahydronaphthyl, each of which may optionally be substituted with 1-4substituents, such as alkyl, trifluoromethyl, cycloalkyl, halogen,hydroxy, alkoxy, acyl, alkyl-C(O)—O—, aryl-O—, heteroaryl-O—, amino,thiol, alkyl-S—, aryl-S-nitro, cyano, carboxy, alkyl-O—C(O)—, carbamoyl,alkyl-S(O)—, sulfonyl, sulfonamido, phenyl, and heterocyclyl.

As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl isdefined herein above. Representative examples of alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- andthe like. Typically, alkoxy groups have about 1-7, more preferably about1-4 carbons.

As used herein, the term “heterocycle,” “heterocycloalkyl” or“heterocyclo” refers to a saturated or unsaturated non-aromatic ring orring system, e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-,8-, 9-, 10-, 11-, or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or15-membered tricyclic ring system and contains at least one heteroatomselected from O, S and N, where the N and S can also optionally beoxidized to various oxidation states. The heterocyclic group can beattached at a heteroatom or a carbon atom. The heterocyclyl can includefused or bridged rings as well as spirocyclic rings. Examples ofheterocycles include tetrahydrofuran, dihydrofuran, 1,4-dioxane,morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane,imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran,dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane,oxathiane, thiomorpholine, azetidine, thiazolidine, morpholine, and thelike.

As used herein, the term “cycloalkyl” refers to saturated or partiallyunsaturated monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12carbon atoms. For the avoidance of doubt, cycloalkyl is not intended toinclude aromatic groups such as naphthylene or phenyl. Unless otherwiseprovided, cycloalkyl refers to cyclic hydrocarbon groups having between3 and 9 ring carbon atoms or between 3 and 7 ring carbon atoms, each ofwhich can be optionally substituted with one, or two, or three, or moresubstituents independently selected from the group consisting of alkyl,halo, oxo, hydroxy, alkoxy, alkyl-C(O)—, acylamino, carbamoyl,alkyl-NH—, (alkyl)₂N—, thiol, alkyl-S—, nitro, cyano, carboxy,alkyl-O—C(O)—, sulfonyl, sulfonamido, sulfamoyl, and heterocyclyl.Exemplary monocyclic hydrocarbon groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl and the like. Exemplary bicyclic hydrocarbon groups includebornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2.2.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groupsinclude adamantyl and the like. The term “hydroxy cycloalkyl” refersspecifically to a cycloalkyl group substituted with one or more hydroxygroups.

As used herein, the term “heteroaryl” refers to a 5-14 memberedmonocyclic- or bicyclic- or tricyclic-aromatic ring system, having 1 to8 heteroatoms selected from N, O and S. In certain preferred aspects,the heteroaryl is a 5-10 membered ring system (e.g., 5-7 memberedmonocycle or an 8-10 membered bicycle) or a 5-7 membered ring system.Exemplary monocyclic heteroaryl groups include 2- or 3-thienyl, 2- or3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazol, 2-, 4-, or5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, and 2-, 4-, and5-pyrimidinyl. Exemplary bicyclic heteroaryl groups include 1-, 3-, 4-,5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl,1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 1-, 2-, 4-, 5-, 6-, 7-, or8-benzimidazolyl and 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-indolyl.

The term “heteroaryl” also refers to a group in which a heteroaromaticring is fused to one or more aryl, cycloaliphatic, or heterocyclylrings, where the radical or point of attachment is on the heteroaromaticring

As used herein, the term “halogen” or “halo” refers to fluoro, chloro,bromo, and iodo.

As used herein, the term “optionally substituted” unless otherwisespecified refers to a group that is unsubstituted or is substituted withone or more, typically 1, 2, 3 or 4, suitable non-hydrogen substituents.If the identity of the “optional substituent” is not clearly defined incontext of the optionally substituted group, then each optionalsubstituent is independently selected from the group consisting of:alkyl, hydroxy, halogen, oxo, amino, alkylamino, dialkylamino, alkoxy,cycloalkyl, CO₂H, heterocycloalkyloxy (which denotes a heterocyclicgroup bonded through an oxygen bridge), —CO₂alkyl, mercapto, nitro,cyano, sulfamoyl, sulfonamide, aryl, —OC(O)alkyl, —OC(O)aryl, aryl-S—,aryloxy; alkylthio, formyl (i.e., HC(O)—), —C(O)NH₂, aralkyl (alkylsubstituted with aryl), aryl and aryl substituted with alkyl,cycloalkyl, alkoxy, hydroxy, amino, alkyl-C(O)—NH—, alkylamino,dialkylamino or halogen. It is understood that where a group isindicated to be optionally substituted, the disclosure includesembodiments in which the group is unsubstituted as well as embodimentsin which the group is substituted.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The term is used todesignate a racemic mixture where appropriate. The use of “rel”indicates that the diastereomeric orientation is known but the absolutestereochemistry is not. In cases where the absolute stereochemistry hasnot been determined the optical rotation and/or chiral chromatographyconditions will indicate which isomer is present.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other. The absolutestereochemistry is specified according to the Cahn-Ingold-Prelog R-Ssystem. When a compound is a pure enantiomer the stereochemistry at eachchiral carbon may be specified by either R or S. Resolved compoundswhose absolute configuration is unknown can be designated (+) or (−)depending on the direction (dextro- or levorotatory) which they rotateplane polarized light at the wavelength of the sodium D line orretention time on chiral chromatography separation. Certain of thecompounds described herein contain one or more asymmetric centers oraxes and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or with the (+) or (−) sign. Thepresent invention is meant to include all such possible isomers,including racemic mixtures, optically pure forms and intermediatemixtures. Optically active (R)- and (S)-isomers may be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques. If the compound contains a double bond, the substituent maybe E or Z configuration. If the compound contains a disubstitutedcycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration. Certain compounds provided in the disclosurecomprise a fused bicyclic ring system, e.g.,2-substituted-N-cyano-7-azanorbornane also known as2-substituted-7-azabicyclo[2.2.1]heptane-7-carbonitrile. Fused bicyclicring systems may be present in endo or exo configuration. In certainaspects, the disclosure provides compounds comprising anendo-N-cyano-7-azanorbornane moiety.

It is understood that for any compound provided herein, including anycompound of Formula (I), or any embodiment thereof, or any compound ofTable A. or a salt of any of the foregoing, the compound may exist inany stereochemical form, such as a single enantiomer, diastereomer, ortautomer or a mixture of one or more enantiomers, diastereomers, andtautomers in any ratio.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the invention. “Salts” include inparticular “pharmaceutical acceptable salts”. The term “pharmaceuticallyacceptable salts” refers to salts that retain the biologicaleffectiveness and properties of the compounds of this invention and,which typically are not biologically or otherwise undesirable. In manycases, the compounds of the present invention are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, gly colic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,benzenesuflonic acid, toluenesulfonic acid, sulfosalicylic acid, and thelike.

Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper. In certainother embodiments, the salts are selected from ammonium, potassium,sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

In another aspect, the present invention provides compounds as disclosedherein in acetate, ascorbate, adipate, aspartate, benzoate, besylate,bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate,camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate,citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate,glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide,isethionate, lactate, lactobionate, laurylsulfate, malate, maleate,malonate, mandelate, mesylate, methylsulphate, mucate, naphthoate,napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate,palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate,poly galacturonate, propionate, sebacate, stearate, succinate,sulfosalicylate, sulfate, tartrate, tosylate trifenatate,trifluoroacetate or xinafoate salt form. In yet another aspect, thepresent invention provides compounds as disclosed herein in C₁-C₄alkylsulfonic acid, benzenesulfonic acid or mono-, di- or tri-C₁-C₄alkylsubstituted benzene sulfonic acid addition salt form.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁴I, ¹²⁵Irespectively. The invention includes various isotopically labeledcompounds as defined herein, for example those into which radioactiveisotopes, such as ³H, ¹³C, and ¹⁴C, are present. Such isotopicallylabelled compounds are useful in metabolic studies (with ¹⁴C), reactionkinetic studies (with, for example ²H or ³H), detection or imagingtechniques, such as positron emission tomography (PET) or single-photonemission computed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or labeled compound may be particularly desirable forPET or SPECT studies. Isotopically labeled compounds of this inventionand salts thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I). The concentration of sucha heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has at least 50%deuterium incorporation at each designated deuterium atom, 60% deuteriumincorporation, at least 75% deuterium incorporation, at least 90%deuterium incorporation, at least 95% deuterium incorporation, at least99% deuterium incorporation, or at least 99.5% deuterium incorporation.

The compounds of the present invention may inherently or by design formsolvates with solvents (including water). Therefore, it is intended thatthe invention embrace both solvated and unsolvated forms. The term“solvate” refers to a molecular complex of a compound of the presentinvention (including salts thereof) with one or more solvent molecules.Such solvent molecules are those commonly used in the pharmaceuticalart, which are known to be innocuous to a recipient, e.g., water,ethanol, dimethylsulfoxide, acetone and other common organic solvents.The term “hydrate” refers to a molecular complex comprising a compoundof the invention and water. Pharmaceutically acceptable solvates inaccordance with the invention include those wherein the solvent ofcrystallization may be isotopically substituted, e.g. D₂O, d₆-acetone,d₆-DMSO.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviating,inhibiting, preventing and/or ameliorating a condition, or a disorder,or a disease or biological process (i) mediated by USP30 activity, or(ii) associated with USP30 activity; or (2) inhibiting the activity ofUSP30. In another non-limiting embodiment, the term “a therapeuticallyeffective amount” refers to the amount of the compound of the presentinvention that, when administered to a cell, or a tissue, or anon-cellular biological material, or a medium, is effective to at leastpartially inhibit USP30 activity.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice, fish, birds and the like. In certain embodiments, the subject is aprimate. In yet other embodiments, the subject is a human.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment to ameliorating the diseaseor disorder (i.e., slowing or arresting or reducing the development ofthe disease or at least one of the clinical symptoms thereof). Inanother embodiment “treat”, “treating” or “treatment” refers toalleviating or ameliorating at least one physical parameter includingthose which may not be discernible by the patient. In yet anotherembodiment “treat”, “treating” or “treatment” refers to modulating thedisease or disorder, either physically, (e.g., stabilization of adiscernible symptom), physiologically, (e.g., stabilization of aphysical parameter), or both.

As used herein, the term “prevent” “preventing” or “prevention” of anydisease or disorder refers in one embodiment, to delay or avoidance ofonset of the disease or disorder (i.e., slowing or preventing the onsetof the disease or disorder in a patient susceptible to development ofthe disease or disorder).

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. Substituents at atoms with unsaturatedbonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high performance liquidchromatography (HPLC) or supercritical fluid chromatography (SFC) usinga chiral adsorbent.

Mixtures of isomers obtainable according to the invention can beseparated in a manner known to those skilled in the art into theindividual isomers; diastereoisomers can be separated, for example, bypartitioning between polyphasic solvent mixtures, recrystallizationand/or chromatographic separation, for example over silica gel or bye.g. medium pressure liquid chromatography over a reversed phase column,and racemates can be separated, for example, by the formation of saltswith optically pure salt-forming reagents and separation of the mixtureof diastereoisomers so obtainable, for example by means of fractionalcrystallization, or by chromatography over optically active columnmaterials.

Within the scope of this text, only a readily removable group that isnot a constituent of the particular desired end product of the compoundsof the present invention is designated a “protecting group”, unless thecontext indicates otherwise. The protection of functional groups by suchprotecting groups, the protecting groups themselves, and their cleavagereactions are described for example in standard reference works, such asJ. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press.London and New York 1973, in T. W. Greene and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”. Third edition. Wiley, New York 1999, in“The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), AcademicPress, London and New York 1981, in “Methoden der organischen Chemie”(Methods of Organic Chemistry), Houben Weyl, 4th edition. Volume 15/I,Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jeschkeit,“Aminosauren, Peptide, Proteine” (Amino acids, Peptides, Proteins),Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in JochenLehmann, “Chemie der Kohlenhydrate: Monosaccharide and Derivate”(Chemistry of Carbohydrates: Monosaccharides and Derivatives), GeorgThieme Verlag. Stuttgart 1974. A characteristic of protecting groups isthat they can be removed readily (i.e. without the occurrence ofundesired secondary reactions) for example by solvolysis, reduction,photolysis or alternatively under physiological conditions (e.g. byenzymatic cleavage).

Intermediates and final products can be worked up and/or purifiedaccording to standard methods, e.g. using chromatographic methods,distribution methods, (re-) crystallization, and the like.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

Any process steps disclosed herein can be carried out under reactionconditions that are known to those skilled in the art, including thosementioned specifically, in the absence or, customarily, in the presenceof solvents or diluents, including, for example, solvents or diluentsthat are inert towards the reagents used and dissolve them, in theabsence or presence of catalysts, condensation or neutralizing agents,for example ion exchangers, such as cation exchangers, e.g. in the H⁺form, depending on the nature of the reaction and/or of the reactants atreduced, normal or elevated temperature, for example in a temperaturerange of from about −100° C. to about 250° C. including, for example,from approximately −80° C. to approximately 250° C., for example at from−80 to −60° C., at room temperature, at from −20 to 40° C. or at refluxtemperature, under atmospheric pressure or in a closed vessel, whereappropriate under pressure, and/or in an inert atmosphere, for exampleunder an argon or nitrogen atmosphere.

The solvents from which those solvents that are suitable for anyparticular reaction may be selected include those mentioned specificallyor, for example, water, esters, such as lower alkyl-lower alkanoates,for example ethyl acetate, ethers, such as aliphatic ethers, for examplediethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane,liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, suchas methanol ethanol or 1- or 2-propanol, nitriles, such as acetonitrile,halogenated hydrocarbons, such as methylene chloride or chloroform, acidamides, such as dimethylformamide or dimethyl acetamide, bases, such asheterocyclic nitrogen bases, for example pyridine orN-methylpyrrolidin-2-one, carboxylic acid anhydrides, such as loweralkanoic acid anhydrides, for example acetic anhydride, cyclic, linearor branched hydrocarbons, such as cyclohexane, hexane or isopentane,methycyclohexane, or mixtures of those solvents, for example aqueoussolutions, unless otherwise indicated in the description of theprocesses. Such solvent mixtures may also be used in working up, forexample by chromatography or partitioning.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In a further embodiment, the composition comprisesat least two pharmaceutically acceptable carriers, such as thosedescribed herein. For purposes of the present invention, unlessdesignated otherwise, solvates and hydrates are generally consideredcompositions. Preferably, pharmaceutically acceptable carriers aresterile. The pharmaceutical composition can be formulated for particularroutes of administration such as oral administration, parenteraladministration, and rectal administration, etc. In addition, thepharmaceutical compositions of the present invention can be made up in asolid form (including without limitation capsules, tablets, pills,granules, powders or suppositories), or in a liquid form (includingwithout limitation solutions, suspensions or emulsions). Thepharmaceutical compositions can be subjected to conventionalpharmaceutical operations such as sterilization and/or can containconventional inert diluents, lubricating agents, or buffering agents, asw ell as adjuvants, such as preservatives, stabilizers, wetting agents,emulsifiers and buffers, etc.

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, and the like and combinations thereof, as would be known to thoseskilled in the art (see, for example. Remington's PharmaceuticalSciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Exceptinsofar as any conventional carrier is incompatible with the activeingredient, its use in the therapeutic or pharmaceutical compositions iscontemplated.

Typically, the pharmaceutical compositions are tablets or gelatincapsules comprising the active ingredient together with one or more of:a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearicacid, its magnesium or calcium salt and/or poly ethyleneglycol; fortablets also c) binders, e.g., magnesium aluminum silicate, starchpaste, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose and/or polyvinylpyrrolidone; if desired d)disintegrates, e.g., starches, agar, alginic acid or its sodium salt, oreffervescent mixtures; and e) absorbents, colorants, flavors andsweeteners. Tablets may be either film coated or enteric coatedaccording to methods known in the art. Suitable compositions for oraladministration include an effective amount of a compound of theinvention in the form of tablets, lozenges, aqueous or oily suspensions,dispersible powders or granules, emulsion, hard or soft capsules, orsyrups or elixirs. Compositions intended for oral use are preparedaccording to any method known in the art for the manufacture ofpharmaceutical compositions and such compositions can contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tablets maycontain the active ingredient in admixture with nontoxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate, granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil. Certain injectablecompositions are aqueous isotonic solutions or suspensions, andsuppositories are advantageously prepared from fatty emulsions orsuspensions. Said compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, they may also contain other therapeuticallyvaluable substances. Said compositions are prepared according toconventional mixing, granulating or coating methods, respectively, andcontain about 0.1-75%, or contain about 1-50%, of the active ingredient.Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orspray able formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives. Asused herein a topical application may also pertain to an inhalation orto an intranasal application. They may be conveniently delivered in theform of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurized container, pump, spray, atomizer ornebulizer, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water may facilitate thedegradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are packaged usingmaterials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e.g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

Prophylactic and Therapeutic Uses

The compounds disclosed herein in free form or in pharmaceuticallyacceptable salt form, exhibit valuable pharmacological properties, e.g.USP30 protein modulating properties and more particularly inhibition ofUSP30 protein activity, e.g. as indicated in in vitro and in vivo testsas provided in the next sections and are therefore indicated fortherapy.

The present invention provides methods of treating a disease or disorderassociated with USP30 protein activity by administering to a subject inneed thereof an effective amount of a compound disclosed herein. Incertain aspects, diseases and disorders associated with mitochondrialdysregulation are suitable for therapy by administration of a compoundof the invention. In certain aspects, the disease or disorder suitablefor therapy by administration of the compound of the invention include,but are not limited to, neurodegenerative diseases, cancer, diabetes,metabolic disorders, cardiovascular disease, psychiatric disease andosteoarthritis. In certain instances, the patient is suffering from CNSdisorder, neurodegenerative disease, multiple sclerosis, mitochondrialmyopathy, encephalopathy, lactic acidosis, stroke-like episodes, Leber'shereditary optic neuropathy, cancer, neuropathy, ataxia, retinitispigmentosa, maternally inherited Leigh syndrome, Danon disease,diabetes, diabetic nephropathy, metabolic disorders, heart failure,ischemic heart disease leading to myocardial infarction, psychiatricdisease, schizophrenia, multiple sulfatase deficiency, mucolipidosis II,mucolipidosis III, mucolipidosis IV, GMI-gangliosidosis, neuronalceroid-lipofuscinoses. Alpers disease, Barth syndrome. Beta-oxidationdefects, carnitine-acyl-carnitine deficiency, carnitine deficiency,creatine deficiency syndromes, co-enzyme Q10 deficiency, complex Ideficiency, complex II deficiency, complex III deficiency, complex IVdeficiency, complex V deficiency. COX deficiency, chronic progressiveexternal ophthalmoplegia syndrome, CPT I deficiency, CPT II deficiency,glutaric aciduria type II, Kearns-Sayre syndrome, lactic acidosis,long-chain acyl-CoA dehydrogenase deficiency, Leigh disease or syndrome,lethal infantile cardiomyopathy, Luft disease, glutaric aciduria type ILmedium-chain acyl-CoA dehydrogenase deficiency, myoclonic epilepsy andragged-red fiber syndrome, mitochondrial cytopathy, mitochondrialrecessive ataxia syndrome, mitochondrial DNA depletion syndrome,myoneurogastointestinal disorder and encephalopathy, Stiff Personsyndrome, pyruvate dehydrogenase deficiency, pyruvate carboxylasedeficiency, POLG mutations, medium/short-chain 3-hydroxyacyl-CoAdehydrogenase deficiency, very long-chain acyl-CoA dehydrogenasedeficiency, and age-dependent decline in cognitive function and musclestrength. In certain embodiments, the disease or disorder suitable fortherapy by administration of a compound of the invention includeParkinson's disease. Alzheimer's disease, amyotrophic lateral sclerosis,Huntington's disease, ischemia, stroke, dementia with Lewy bodies,frontotemporal dementia, autosomal recessive juvenile Parkinson'sdisease where parkin is mutated and Parkinson's disease related tomutations in-α synuclein, parkin and PINK1. In certain aspects, methodsof treating Parkinson's disease by administration of a compound of theinvention to a patient are provided.

In a specific embodiment, the present invention provides a method oftreating or preventing a neurodegenerative disease by administering to asubject in need thereof an effective amount of a compound disclosedherein. In certain embodiments, patients who are currently asymptomaticbut are at risk of developing neurodegenerative disease are suitable foradministration with a compound of the invention. The methods of treatingor preventing neurodegenerative disease include, but are not limited to,methods of treating or preventing Parkinson's disease, Alzheimer'sdisease, amyotrophic lateral sclerosis, Huntington's disease, ischemia,stroke, dementia with Lewy bodies, frontotemporal dementia, autosomalrecessive juvenile Parkinson's disease where parkin is mutated andParkinson's disease related to mutations in α-synuclein, parkin andPINK1. In certain aspects, the methods of treating or preventingneurodegenerative diseases provided include methods of treatingParkinson's disease.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution. The dosage in vitro may range between about 10⁻³ molar and10⁻⁹ molar concentrations. A therapeutically effective amount in vivomay range depending on the route of administration, between about0.1-500 mg/kg, or between about 1-100 mg/kg.

The activity of a compound according to the present invention can beassessed by in vitro & in vivo methods, such as those described in theexamples below.

The compound of the present invention may be administered eithersimultaneously with, or before or after, one or more other therapeuticagent. The compound of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the other agents.

In one embodiment the invention provides a product comprising a compounddisclosed herein and at least one other therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use in therapy. Inone embodiment the therapy is the treatment of a disease or conditionmediated by USP30 protein activity. In preferred aspects, the therapy isa treatment for a neurodegenerative disease, including, but not limitedto, Parkinson's disease, Alzheimer's disease, amyotrophic lateralsclerosis, Huntington's disease, ischemia, stroke, dementia with Lewybodies, frontotemporal dementia, autosomal recessive juvenileParkinson's disease where parkin is mutated and Parkinson's diseaserelated to mutations in α-synuclein, parkin and PINK1.

Products provided as a combined preparation include a compositioncomprising the compound disclosed herein and the other therapeuticagent(s) together in the same pharmaceutical composition, or thecompound disclosed herein and the other therapeutic agent(s) in separateform, e.g. in the form of a kit.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound as disclosed herein and another therapeuticagent(s). Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable carrier, as described above.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound disclosed herein. In one embodiment, the kit comprises meansfor separately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent.

Accordingly, the invention provides the use of a compound as disclosedherein for treating a disease or condition mediated by USP30 proteinactivity wherein the medicament is prepared for administration withanother therapeutic agent. The invention also provides the use ofanother therapeutic agent for treating a disease or condition mediatedby USP30 protein activity, wherein the medicament is administered with acompound as disclosed herein. In another aspect, the invention providesthe use of a compound as disclosed herein for treating aneurodegenerative disease or disorder selected from Parkinson's disease,Alzheimer's disease, amyotrophic lateral sclerosis, Huntington'sdisease, ischemia, stroke, dementia with Lewy bodies, frontotemporaldementia, autosomal recessive juvenile Parkinson's disease where parkinis mutated and Parkinson's disease related to mutations in a synuclein,parkin and PINK1, wherein the medicament is prepared for administrationwith another therapeutic agent. The invention also provides the use ofanother therapeutic agent for treating a disease or disorder selectedfrom Parkinson's disease. Alzheimer's disease, amyotrophic lateralsclerosis. Huntington's disease, ischemia, stroke, dementia with Lewybodies, frontotemporal dementia, autosomal recessive juvenileParkinson's disease where parkin is mutated and Parkinson's diseaserelated to mutations in a synuclein, parkin and PINK1, wherein themedicament is administered with a compound as disclosed herein.

The invention also provides a compound as disclosed herein for use in amethod of treating a disease or condition mediated by USP30 proteinactivity wherein the compound is prepared for administration withanother therapeutic agent. The invention also provides anothertherapeutic agent for use in a method of treating a disease or conditionmediated by USP30 protein activity, wherein the other therapeutic agentis prepared for administration with a compound as disclosed herein. Theinvention also provides a compound as disclosed herein for use in amethod of treating a disease or condition mediated by USP30 proteinactivity, wherein the compound is administered with another therapeuticagent. The invention also provides another therapeutic agent for use ina method of treating a disease or condition mediated by USP30 proteinactivity, wherein the other therapeutic agent is administered with acompound as disclosed herein.

The invention also provides the use of a compound as disclosed hereinfor treating a disease or condition mediated by USP30 protein activitywherein the patient has previously (e.g. within 24 hours) been treatedwith another therapeutic agent. The invention also provides the use ofanother therapeutic agent for treating a disease or condition mediatedby USP30 protein activity wherein the patient has previously (e.g.within 24 hours) been treated with a compound as disclosed herein.

The pharmaceutical compositions can be administered alone or incombination with other molecules known to have a beneficial effect intreatment of USP30 mediated disease or mote particularly in thetreatment of diseases associated with mitochondrial dysfunction and/orneurodegenerative disease. In certain aspects, the pharmaceuticalcompositions provided may be administered alone or in combination withother molecules known to have a beneficial effect in treatment of adisease or disorder selected from CNS disorder, neurodegenerativedisease, multiple sclerosis, mitochondrial myopathy, encephalopathy,lactic acidosis, stroke-like episodes, Leber's hereditary opticneuropathy, cancer, neuropathy, ataxia, retinitis pigmentosa, maternallyinherited Leigh syndrome, Danon disease, diabetes, diabetic nephropathy,metabolic disorders, heart failure, ischemic heart disease leading tomyocardial infarction, psychiatric disease, schizophrenia, multiplesulfatase deficiency, mucolipidosis II, mucolipidosis III, mucolipidosisIV, GMI-gangliosidosis, neuronal ceroid-lipofuscinoses, Alpers disease,Barth syndrome, Beta-oxidation defects, carnitine-acyl-carnitinedeficiency, carnitine deficiency, creatine deficiency syndromes,co-enzyme Q10 deficiency, complex I deficiency, complex II deficiency,complex III deficiency, complex IV deficiency, complex V deficiency, COXdeficiency, chronic progressive external ophthalmoplegia syndrome, CPT Ideficiency, CPT II deficiency, glutaric aciduria type II, Kearns-Sayresyndrome, lactic acidosis, long-chain acyl-CoA dehydrogenase deficiency,Leigh disease or syndrome, lethal infantile cardiomyopathy, Luftdisease, glutaric aciduria type II, medium-chain acyl-CoA dehydrogenasedeficiency, myoclonic epilepsy and ragged-red fiber syndrome,mitochondrial cytopathy, mitochondrial recessive ataxia syndrome,mitochondrial DNA depletion syndrome, myoneurogastointestinal disorderand encephalopathy, Stiff Person syndrome, pyruvate dehydrogenasedeficiency, pyruvate carboxylase deficiency, POLG mutations,medium/short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, verylong-chain acyl-CoA dehydrogenase deficiency, and age-dependent declinein cognitive function and muscle strength. In certain aspects, thepharmaceutical composition has a beneficial effect in the treatment of aneurodegenerative disease selected from Parkinson's disease, Alzheimer'sdisease, amyotrophic lateral sclerosis, Huntington's disease, ischemia,stroke, dementia with Lewy bodies, frontotemporal dementia, autosomalrecessive juvenile Parkinson's disease where parkin is mutated andParkinson's disease related to mutations in α-synuclein, parkin andPINK1. A combination therapy regimen may be additive, or it may producesynergistic results (e.g., improvement in mitochondrial function whichis more than expected for the combined use of the two agents). In someembodiments, the present invention provide a combination therapy forpreventing and/or treating USP30 mediated disease or more particularlyParkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis,Huntington's disease, ischemia, stroke, dementia with Lewy bodies,frontotemporal dementia, autosomal recessive juvenile Parkinson'sdisease where parkin is mutated and Parkinson's disease related tomutations in α-synuclein, parkin and PINK1 with a compound of theinvention and a second therapeutic agent. In some aspects, the secondtherapeutic agent is selected from dopamine agonists (such as levodopa),dopamine receptor agonists (such as pramipexole), Mao-B inhibitors (suchas rasagiline), catechol-O-methyltransferase (COMT) inhibitors (such asentacapone), glucosylceramide synthase inhibitors (such asGenzyme—GZ/SAR402671), and glucosylcerebrosidase chaperones (such asLysosomal Therapeutics—LT1291).

In one embodiment, the invention provides a method of inhibiting theactivity of USP30, in a subject, wherein the method comprisesadministering to the subject a therapeutically effective amount of thecompound according to the definition of Formula (I). The inventionfurther provides methods of inhibiting the activity of USP30 protein ina subject by administering a compound as disclosed herein, wherein themethod comprises administering to the subject a therapeuticallyeffective amount of the compound as disclosed herein.

In one embodiment, the invention provides a compound as disclosedherein, for use as a medicament.

In one embodiment, the invention provides the use of a compound asdisclosed herein for the treatment of a disorder or disease in a subjectcharacterized by the activity of USP30. In particular, the inventionprovides the use of a compound as disclosed herein for the treatment ofa disorder or disease mediated by the activity of USP30, e.g., adisorder or disease mediated by mitochondrial dysfunction such asParkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis,Huntington's disease, ischemia, stroke, dementia with Lewy bodies,frontotemporal dementia, autosomal recessive juvenile Parkinson'sdisease where parkin is mutated and Parkinson's disease related tomutations in α-synuclein, parkin and PINK1. In certain preferredaspects, the invention provides for the use of a compound as disclosedherein for the treatment of Parkinson's disease.

In one embodiment, the invention provides the use of a compound asdisclosed herein in the manufacture of a medicament for the treatment ofa disorder or disease in a subject characterized by activity of USP30.More particularly in the manufacture of a medicament for the treatmentof a disease or disorder in a subject characterized by activity ofUSP30, e.g., a disorder or disease mediated by mitochondrial dysfunctionsuch as Parkinson's disease, Alzheimer's disease, amyotrophic lateralsclerosis, Huntington's disease, ischemia, stroke, dementia with Lewybodies, frontotemporal dementia, autosomal recessive juvenileParkinson's disease where parkin is mutated and Parkinson's diseaserelated to mutations in α-synuclein, parkin and PINK1. In certainpreferred aspects, the invention provides the use of a compound asdisclosed herein in the manufacture of a medicament for the treatment ofParkinson's disease.

In one embodiment, the invention provides the use of a compound asdisclosed herein for the treatment of a disorder or disease in a subjectcharacterized by activity of USP30. More particularly, the inventionprovides uses of the compounds provided herein in the treatment of adisease or disorder characterized by activity of USP30, e.g., a disorderor disease mediated by mitochondrial dysfunction such as Parkinson'sdisease, Alzheimer's disease, amyotrophic lateral sclerosis,Huntington's disease, ischemia, stroke, dementia with Lewy bodies,frontotemporal dementia, autosomal recessive juvenile Parkinson'sdisease where parkin is mutated and Parkinson's disease related tomutations in α-synuclein, parkin and PINK1. In certain embodiments, theuses of the compounds provided herein is for the treatment ofParkinson's disease.

In a specific embodiment, the present invention provides use of thecompounds of the invention for treating or preventing CNS disorder,neurodegenerative disease, multiple sclerosis, mitochondrial myopathy,encephalopathy, lactic acidosis, stroke-like episodes, Leber'shereditary optic neuropathy, cancer, neuropathy, ataxia, retinitispigmentosa, maternally inherited Leigh syndrome, Danon disease,diabetes, diabetic nephropathy, metabolic disorders, heart failure,ischemic heart disease leading to myocardial infarction, psychiatricdisease, schizophrenia, multiple sulfatase deficiency, mucolipidosis II,mucolipidosis III, mucolipidosis IV, GMI-gangliosidosis, neuronalceroid-lipofuscinoses, Alpers disease, Barth syndrome. Beta-oxidationdefects, carnitine-acyl-carnitine deficiency, carnitine deficiency,creatine deficiency syndromes, co-enzyme Q10 deficiency, complex Ideficiency, complex II deficiency, complex III deficiency, complex IVdeficiency, complex V deficiency, COX deficiency, chronic progressiveexternal ophthalmoplegia syndrome. CPT I deficiency, CPT II deficiency,glutaric aciduria type II, Kearns-Sayre syndrome, lactic acidosis,long-chain acyl-CoA dehydrogenase deficiency. Leigh disease or syndrome,lethal infantile cardiomyopathy. Luft disease, glutaric aciduria typeII, medium-chain acyl-CoA dehydrogenase deficiency, myoclonic epilepsyand ragged-red fiber syndrome, mitochondrial cytopathy, mitochondrialrecessive ataxia syndrome, mitochondrial DNA depletion syndrome,myoneurogastointestinal disorder and encephalopathy, Stiff Personsyndrome, pyruvate dehydrogenase deficiency, pyruvate carboxylasedeficiency, POLG mutations, medium/short-chain 3-hydroxyacyl-CoAdehydrogenase deficiency, very long-chain acyl-CoA dehydrogenasedeficiency, and age-dependent decline in cognitive function and musclestrength. In certain embodiments, patients w ho are currentlyasymptomatic but are at risk of developing a disorder or diseasemediated by mitochondrial dysfunction such as Parkinson's disease.Alzheimer's disease, amyotrophic lateral sclerosis, Huntington'sdisease, ischemia, stroke, dementia with Lewy bodies, frontotemporaldementia, autosomal recessive juvenile Parkinson's disease where parkinis mutated and Parkinson's disease related to mutations in a synuclein,parkin and PINK1 are suitable for administration with a compound of theinvention. The use in treating or preventing a disorder or diseasemediated by mitochondrial dysfunction such as Parkinson's disease.Alzheimer's disease, amyotrophic lateral sclerosis, Huntington'sdisease, ischemia, stroke, dementia with Lewy bodies, frontotemporaldementia, autosomal recessive juvenile Parkinson's disease where parkinis mutated and Parkinson's disease related to mutations in α-synuclein,parkin and PINK1 include, but are not limited to, uses in treating orpreventing one or more symptoms or aspects of disorder or diseasemediated by mitochondrial dysfunction.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure materials.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade (° C.). If not mentioned otherwise, allevaporations are performed under reduced pressure, typically betweenabout 15 mm Hg and 100 mm Hg (=20-133 mbar). The structure of finalproducts, intermediates and starting materials is confirmed by standardanalytical methods, e.g., microanalysis and spectroscopiccharacteristics, e.g., MS, IR, NMR. Abbreviations used are thoseconventional in the art.

The invention relates also to those forms of the process in which acompound obtainable as an intermediate at any stage of the process isused as starting material and the remaining process steps are carriedout, or in which a starting material is formed under the reactionconditions or is used in the form of a derivative, for example in aprotected form or in the form of a salt, or a compound obtainable by theprocess according to the invention is produced under the processconditions and processed further in situ.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents and catalysts utilized to synthesize thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art.

Unless otherwise noted, all materials were obtained from commercialsuppliers and used without further purification. All parts are by weightand temperatures are in degrees centigrade unless otherwise indicated.All microwave assisted reactions were conducted with a Smith Synthesizerfrom Biotage. Mass spectral data was determined by electrosprayionization technique. Unless otherwise stated, reactions were run atroom temperature.

Commercially available materials were purchased from Millipore-Sigma,HDH Pharma, Pharmablock, Alfa Aesar, Enovation Chemicals, Combi-Blocks,and other suppliers as stated.

Compound names, i.e., IUPAC names, for compounds described in theinstant application were generated using ChemDraw compound namingsoftware.

The following abbreviations are used:

-   ACN—Acetonitrile-   CDI—1,1′-carbonyldiimidazole-   DCM—dichloromethane-   DMSO—dimethyl sulfoxide-   DMF—N,N-dimethylformamide-   THF—tetrahydrofuran-   Et₂O—diethyl ether-   EtOAc—ethyl acetate-   EtOH—ethyl alcohol-   HATU—1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate,    N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanamimum    hexafluorophosphate N-oxide-   Hunig's base or DIEA—N,N-Diisopropylethylamine-   LiOH—lithium hydroxide-   Ms—mesylate-   MeCN—acetonitrile-   MeOH—methyl alcohol-   NaOH—sodium hydroxide-   ppt—precipitate-   Rbf—round bottom flask-   rt—room temperature-   RuPhos Pd    G1—Chloro-(2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)-methyl-t-butyl    ether adduct-   SFC—supercritical fluid chromatography-   sm—starting material-   T3P—Propylphosphonic anhydride solution-   TFA—trifluoroacetic acid-   tmp—2,2,6,6-tetramethylpiperidine-   h—hour-   min—min-   rt—room temperature (22-25° C.)-   mL milliliters-   μL microliters-   g grams-   μg micrograms-   mg milligrams-   μmoL micromoles-   μW microwave (heating)

General Method of Preparation

The compounds described herein are prepared using techniques known toone skilled in the art through the reaction sequences depicted inGeneral Methods 1-3 as well as by other methods. Furthermore, in thefollowing schemes, where specific acids, bases, reagents, couplingagents, solvents, etc. are mentioned, it is understood that othersuitable acids, bases, reagents, coupling agents, solvents, etc. may beused and are included within the scope of the present invention.

Compounds can be prepared using general method 1 in which anamino-cyanamide derivative was treated with a carboxylic acid andcoupling reagent such as T3P in the presence of an amine base such astriethylamine and pyridine. Alternatively the compounds could beprepared by treating the amino-cyanamide with base such as triethylamineand an acid chloride as depicted in general method 2.

General method 3 depicts an alternative preparation that utilizes aprotected diamine derivative in coupling conditions as described ingeneral method 1. Deprotection of the resulting amide followed bycyanation with cyanogen bromide in the presence of an inorganic basesuch as potassium carbonate provides the cyanamide.

Analogous amides can be prepared via the method depicted in generalmethod 4 by treatment of a protected amino acid derivative with an amineand a coupling reagent such as T3P in the presence of pyridine. Theresulting protected derivative can then be deprotected and treated withcyanogen bromide and base as in general method 3.

In another general method bromo-acetamide Intermediate B can be reactedwith a heteroatom substituted moiety (R-AH) in the presence of a basesuch as cesium carbonate in a polar aptotic solvent such as DMF asdepicted in General Method 5.

Compounds can also be synthesized via General Method 6 in which acyanamide containing aryl or heteroaryl amine participates in a C—Ncoupling reaction with a heteroaryl-halide and a transition metalcatalyst such as palladium, in complex with supporting ligands such asRuPhos. and a base such as cesium carbonate in polar solvent at elevatedtemperature in a microwave reactor.

Synthetic Intermediates Intermediate A:(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonitrilehydrochloride

Step 1: To a red cap vial was added tert-butylracemic-(1S,2S,4R)-7-azabicyclo[2.2.1]hept-2-ylcarbamate hydrochloride(0.7 g, 2.81 mmol CAS #2098589-06-9) and 4-methoxybenzaldehyde (0.621ml, 5.07 mmol) in dichloromethane (5.63 ml) followed by addition ofsodium triacetoxyborohydride (1.074 g, 5.07 mmol). It was stirred at rtfor 3.5 h. Another 1.5 h later, LCMS showed partial conversion. Thenanother 0.2 g of sodium triacetoxyborohydride was added, and thereaction mixture was stirred at rt for 18 hr. LC/MS showed >90%conversion to desired product. Then water and 10 mL of IN NaOH was addedand the reaction was extracted with DCM. The organic extract was washedwith brine and dried over MgSO₄. The solution was filtered andconcentrated in vacuo to give the crude material as a light-yellow oil.The crude material was absorbed onto a plug of silica gel and purifiedby chromatography through a 25 g biotage ultra column, eluting with agradient of 10% to 40% EtOAc in EtOH (3/1 with 0.5% Et₃N as additive) inHeptane, to provide tert-butylracemic-(1S,2S,4R)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate(0.8 g, 2.406 mmol, 86% yield) as clear oil. m/z: 333.3 [M+1] The samplewas purified by SFC using a Chiralpak AD-H 2×25 cm, 5 micron column, amobile phase of 15% methanol w/ 0.2% diethylamine using a flowrate of 80mL/min. to generate peak 1 with an ee of >99% and peak 2 with an eeof >97%. Peak assignment determined by SFC: Chiralpak AD-H, 15% methanolw/ 0.2% diethylamine. The absolute stereochemistry of the peak 1intermediate was established by X-ray crystallography and peak 1 derivedmaterial was found to have (1R,2R,4S) stereochemistry.

Step 2: To a 25-mL round-bottomed flask was added peak 1 derivedtert-butyl((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate(0.108 g, 0.325 mmol) and K₂CO₃ (0.103 g, 0.747 mmol) in 1,4-dioxane(1.477 ml) followed by addition of cyanogen bromide solution, 5.0 m inacetonitrile (0.130 ml, 0.650 mmol). The reaction mixture was allowed tostir at rt overnight before being quenched with a saturated aqueoussolution of NaHCO₃. The reaction mixture was diluted in CH₂Cl₂ and waterand the lay ers were separated. The aqueous phase was extracted withCH₂Cl₂. The organic extracts were combined and dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The product was useddirectly in the next step, m/z: 260.2 [M+23]

Step 3: To a 50 mL round bottom flask was added crude ten-butyl((1S,2S,4R)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)carbamate (0.414 g,1.745 mmol) and hydrogen chloride solution 4.0 m in dioxane (6.54 ml,26.2 mmol) in 1,4-dioxane (4.36 ml) at 0° C. It was warmed to n andstirred for 1 h. LC/MS showed incomplete conversion. Then another 2 mLof 4.0 M HCl in dioxane was added and the reaction stirred for another25 min. The precipitate was collected by filtration to yield peak 1derived (1S,2S,4R)-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonitrilehydrochloride (0.4 g, 2.304 mmol, 132% yield) as a white solid, m/z:138.2 [M+1] ¹H NMR (500 MHz, DMSO-d₆) δ 8.48 (br s, 3H), 4.25-4.28 (m,1H), 4.20 (t, J=4.74 Hz, 1H), 3.57-3.64 (m, 1H), 2.14-2.21 (m, 1H), 1.96(br d, J=11.16 Hz, 1H), 1.78-1.88 (m, 2H), 1.72-1.78 (m, 1H), 1.41 (brd, J=13.49 Hz, 1H)

An identical procedure for steps 2 and 3 above were used to obtainracemic material from racemic endo-tert-butyl(7-azabicyclo[2.2.1]heptan-2-yl)carbamate (CAS 2098589-06-9) to provideRacemic Intermediate A

Intermediate B:2-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide

Intermediate A (1 g, 2.99 mmol; 52% by weight) was dissolved indichloromethane (14.97 ml). Water (14.97 ml) and K₂CO₃ (0.828 g, 5.99mmol) were added and with vigorous stirring 2-bromoacetyl bromide (0.339ml, 3.89 mmol) was added. After 45 min full conv. was observed and theaq. was separated, extracted 2× with DCM. The combined organics werewashed with brine, dried over Na₂SO₄, and concentrated to provide2-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide(0.9 g, 3.49 mmol, 116% yield) as a viscous oil which was used directly,m/z: 258.0, 261.0 [M+1]

Intermediate C:N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)indoline-5-carboxamidehydrochloride

Step 1:

To a glass reaction vial were added1-(tert-butoxycarbonyl)-5-indolinecarboxylic acid (2.3 g, 8.74 mmol) andoxalyl chloride (1.0 ml, 11.36 mmol) in dichloromethane (17.5 ml)followed by 3 drops of DMF at 0° C. It was stirred at rt for 0.5 h. LCMSproved desired product formation by quenched with MeOH. It wasconcentrated and dried on high vacuum to yield tert-butyl5-(chlorocarbonyl)indoline-1-carboxylate (2.46 g, 8.74 mmol, 100% yield)as brown solid. It was used for next step directly.

Step 2:

To a glass vial were added Intermediate A (0.641 g, 3.69 mmol) andtert-butyl 5-(chlorocarbonyl)indoline-1-carboxylate (0.8 g, 2.84 mmol)in DCM (9.5 ml) followed by triethylamine (14 ml, 9.94 mmol) at 0° C.The reaction was stirred at (t for 0.5 h when LC/MS showed desiredproduct formation. The reaction mixture was diluted with water andextracted with DCM. The combined organics were concentrated and thecrude material was adsorbed onto a plug of silica gel and purified bychromatography through a Biotage 25 g redi-sep ultra, eluting with agradient of 10% to 70% EtOAc in Heptane, to provide tert-butyl5-(((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)indoline-1-carboxylate(0.55 g, 1.438 mmol, 50.6% yield) as white solid, m/z: 383.2 [M+1]

Step 3:

To a round-bottomed flask was added tert-butyl5-(chlorocarbonyl)indoline-1-carboxylate (0.8 g, 2.84 mmol) and hydrogenchloride solution, 4.0 m in dioxane (10.7 ml, 42.6 mmol) in dioxane (5ml) slowly. The reaction mixture was stirred at rt for 3 h. LCMS showedall sm consumed and the white ppt was collected by filtration to yieldN-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)indoline-5-carboxamidehydrochloride (0.59 g, 1.851 mmol, 65.2% yield) as a white solid, m/z:283.2 [M+1]

The intermediates in the table below were made by identical procedures:

Int. Structure Name LC/MS data C-1

4-bromo-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-methylbenzamide m/z: 334.2 [M + 1] C-2

6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1H-indazole-5- carboxamide m/z: 316.0 [M +1] C-3

7-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1H-indole-3- carboxamide m/z: 359.0/361.0[M + 1] C-4

4-bromo-2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)benzamide m/z: 354.0/356.0 [M + 1] C-5

4-bromo-2,6-dichloro-N-(11R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)benzamide m/z: 390.0 [M + 1] C-6

4-bromo-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-(trifluoromethyl)benzamide m/z: 389.0 [M + 1] C-7

4-bromo-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-fluorobenzamide m/z: 339.0 [M + 1] C-8

4-bromo-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-methylbenzo[d]thiazole-7-carboxamide m/z: 393.0 [M + 1]

Intermediate D: 1-(4-methylpyrimidin-2-yl)indoline-5-carboxylic acid

Step 1:

A glass microwave reaction vessel was charged with methylindoline-5-carboxylate (0.06 g, 0.339 mmol), 2-chloro-4-methylpyrimidine(0.054 g, 0.423 mmol),racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.032 g, 0.051mmol), palladium (ii) acetate (7.60 mg, 0.034 mmol) and cesium carbonate(0.221 g, 0.677 mmol) in tetrahydrofuran (1.7 ml). The reaction mixturewas purged with N₂ and heated in a microwave reactor at 110° C. for 10min. LCMS showed desired product. The reaction mixture was diluted withwater and extracted with DCM. The organic extract was washed withsaturated NaCl and dried over MgSO₄. The solution was filtered andconcentrated in vacuo to yield erode product which was used for nextstep directly, m/z: 270.2 [M+1]

Step 2:

To a glass reaction vial containing erode product from step 1 was addedLiOH (1M) (1.35 ml, 1.35 mmol) in MeOH/THF (0.5 ml/0.5 ml, 1:1) andheated to 50° C. for 2 h. It was concentrated and acidified with 2N HCl(aq.) until pH˜2. The white ppt was collected by filtration to yield1-(4-methylpyrimidin-2-yl)indoline-5-carboxylic acid (0.08 g, 0.313mmol, 93% yield) as white solid which was dried on high vacuum and usedin the next step directly, m/z: 256.2 [M+1]

Intermediate E: 1-(4-methylpyrimidin-2-yl)-1H-indazole-5-carboxylic acid

Step 1:

To a glass reaction vial were charged with 2-chloro-4-methylpyrimidine(0.095 g, 0.738 mmol), methyl indazole-5-carboxylate (0.1 g, 0.568mmol),chloro(2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]Pd(ii) (0.058 g, 0.085 mmol) with potassium tert-butoxide (0.159 g, 1.42mmol) in dioxane (2.3 mL). The reaction mixture was purged with N2 gasand heated in heating block at 90° C. 20 min later, LCMS showed nearlyfull conversion to desired product as major product. The orange reactionmixture was diluted with water and extracted with DCM. The organicextract was concentrated in vacuo to give the crude material as anorange solid which was used directly in the next step, m/z: 269.2 [M+1]

Step 2:

To a glass reaction vial containing crude product from step 1 was addedLiOH (1M) (2.3 ml, 2.3 mmol) in MeOH/THF (1:1, 2.2 mL). The mixture washeated to 60° C. for 1.5 h. LCMS showed nearly full conversion todesired product. It was cooled to n and organic solvent was reduced. Tothe red residue was treated with water (˜1 mL), and 2N HCl aq. slowlyuntil pH˜2. The red ppt was collected by filtration and dried on highvacuum and used directly. m/z: 255.2 [M+1]

The intermediates in the table below were made by identical procedures:

Int. Structure Name LC/MS data E-1

4-((4-cyclopropylpyrimidin- 2-yl)amino)-2,5- difluorobenzoic acid m/z:306.0 [M + 1] E-2

4-((4-cyclopropylpyrimidin- 2-yl)amino)-2,3- difluorobenzoic acid m/z:306.1 [M + 1] E-3

1-(6-methylpyridin-2- yl)-1H-indazole-5- carboxylic acid m/z: 254.2 [M +1] E-4

6-chloro-1-(6- methylpyridin-2- yl)-1H-indazole-5- carboxylic acid m/z:288.0 [M + 1] E-5

6-fluoro-1-(6- methylpyridin-2- yl)-1H-indazole-5- carboxylic acid m/z:272.2 [M + 1] E-6

6-chloro-1-(6-(2,2,2- trifluoroethoxy)pyridin-2- yl)-1H-indazole-5-carboxylic acid m/z: 372.0 [M + 1] E-7

6-chloro-1-(1,7- naphthyridin-2- yl)-1H-indazole-5- carboxylic acid m/z:325.0 [M + 1] E-8

6-chloro-1-(6- (cyanomethyl)pyridin-2- yl)-1H-indazole-5- carboxylicacid E-9

6-chloro-1-(1,8- naphthyridin-2- yl)-1H-indazole-5- carboxylic acid m/z:325.0 [M + 1] E-10

1-(6-methylpyridin-2- yl)-4,5,6,7-tetrahydro- 1H-indazole-5- carboxylicacid m/z: 258.1 [M + 1]

Intermediate F: N-Benzyl-N-(3-bromobenzyl)glycine

The mixture of N-benzyl-1-(3-bromophenyl)methanamine (HCl salt, 47 mg,0.15 mmol), tert-butyl 2-bromoacetate (35 mg, 0.18 mmol). K₂CO₃ (aq 2M,0.15 mL, 0.30 mmol), DMSO (0.1 mL) and MeCN (0.5 mL) was stirred at roomtemperature for 6 h. The resulting solution was subjected to preparativeHPLC (0.1% TEA) to afford tert-butyl N-benzyl-N-(3-bromobenzyl)glycinate(60 mg, quantitative). To the mixture of tert-butylN-benzyl-N-(3-bromobenzyl)glycinate obtained in the previous reaction,trifluoroacetic acid (1.0 mL) and dichloromethane (0.5 mL) was stirredat room temperature for 5 h. The resulting mixture was concentrated,dissolved in dichloromethane (2.0 mL), then concentrated again toprovide N-benzyl-N-(3-bromobenzyl)glycine. [M+H] 334.1.

Intermediate G:N-(racemic-(endo)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1H-indole-5-carboxamide

To a glass vial was added racemic Intermediate C (0.08 g, 0.251 mmol)and manganese dioxide (0.218 g, 2.509 mmol) in dichloromethane (1.3 ml)followed by Et₃N (0.070 ml, 0.502 mmol). The reaction was stirred at rtfor 1.5 h. LC/MS showed >90% conversion. The reaction mixture wasfiltered through a celite plug, concentrated, and used for next stepdirectly. m/z: 281.2 [M+1]

Intermediate H: 2-(4-chloro-3-(trifluoromethyl)phenoxy)acetic acid

To a 0.5-2 mL microwave vial were added4-chloro-3-(trifluoromethyl)phenol (0.51 g, 2.59 mmol) and sodiumhydroxide, pellets (0.467 g, 11.68 mmol) in water (2.2 ml). It wasstirred at rt for 5 min and then bromoacetic acid (0.901 g, 6.49 mmol)was added. The mixture was heated in microwave reactor at 120° C. for 10min. The reaction was acidified with 2N aq. HCl until pH˜2. The whiteppt was collected by filtration and dried on high vacuum overnight toyield 2-(4-chloro-3-(trifluoromethyl)phenoxy (acetic acid (0.5 g, 1.964mmol, 76% yield) as white solid.

Intermediate I:racemic-(endo)-7-cyano-7-azabicyclo[2.2.1]heptane-2-carboxylic acid

To a stirred solution ofracemic-(1R,2R,4S)-7-azabicyclo[2.2.1]heptane-2-carboxylic acidcarboxylate (HCl salt, 8.9 mg, 0.050 mmol, purchased from ChemBridge)DIEA (0.026 mL, 0.15 mmol) and methanol (0.5 mL) was added cyanogenbromide (11 mg, 0.10 mmol) in dichloromethane (0.2 mL) at roomtemperature. After stirring for 20 min. the mixture was concentrated toprovideracemic-(1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptane-2-carboxylic acidwhich was used for the next reaction without further purification. MS(EI) for C₈H₁₀N₂O₂, found 167.1 (MH+).

Intermediate J:6-chloro-N-((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methylpyrimidin-2-yl)indoline-5-carboxamide

Step 1:

To a red cap vial was added tert-butyl((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamate(0.5 g, 1.504 mmol) (from intermediate A step 1) and HCl in dioxane (4M)(3.01 ml, 12.03 mmol) in dioxane (3.0 ml). The slurry was stirred at rtfor 4 h when LC/MS showed nearly full conversion to desired product. Thereaction was concentrated and MTBE was added. The mixture was stirred atn until white ppt formed. The white ppt was collected by quickfiltration and dried on high vacuum overnight to yield the desired HClsalt (1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-aminehydrochloride (0.40 g, 1.488 mmol, 99% yield) as a white solid, m/z:233.2 [M+1]

Step 2:

To a vial containing 6-chloro-5-indolinecarboxylic acid (0.15 g, 0.759mmol) was added HATU (0.404 g, 1.063 mmol) and Hunig's base (0.398 ml,2.277 mmol) in DMF (2.9 ml). After stirring for 5 min,(1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-aminehydrochloride (0.265 g, 0.987 mmol) was added. The orange reactionmixture was stirred at rt for 5 min when LCMS showed the desiredproduct. The reaction mixture was treated with 6N NaOH (aq.) andextracted with DCM and the crude material was absorbed onto a plug ofsilica gel and purified by chromatography through a Biotage SNAP KP-NH28 g column, eluting with a gradient of 10% to 35% EtOAc/EtOH (3/1) inHeptane, to provide6-chloro-N-((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)indoline-5-carboxamide(0.13 g, 0.316 mmol, 41.6% yield) as off-white foam, m/z: 412.2 [M+1]

Step 3:

A glass microwave reaction vessel was charged with6-chloro-N-((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)indoline-5-carboxamide(0.06 g, 0.146 mmol), 2-chloro-4-methylpyrimidine (0.028 g, 0.218 mmol),RuPhos Pd G1 methyl r-butyl ether adduct (0.024 g, 0.029 mmol) andcesium carbonate (0.119 g, 0.364 mmol). The reaction vial was purgedwith N₂ and tBuOH (0.73 ml) was added. The reaction mixture was heatedin microwave reactor at 110° C. for 10 min. LCMS showed full conversionto desired product. The reaction mixture was diluted with water andextracted with DCM. The organic extract was concentrated. The crudematerial was absorbed onto a plug of silica gel and purified bychromatography through a 10 g biotage ultra column, eluting with agradient of 10% to 75% EtOAc/EtOH (3/1) in Heptane to provide6-chloro-N-((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methylpyrimidin-2-yl)indoline-5-carboxamide(0.04 g, 0.079 mmol, 54.5% yield) as a yellow foam, m/z: 504.2 [M+1]

The intermediates in the table below were made by identical procedures:

Int. Structure Name LC/MS data J-1

N-((1R,2R,4S)-7-(4- methoxybenzyl)-7- azabicyclo[2.2.1]heptan-2-yl)-1-(quinolin-2-yl)-1H- indazole-5-carboxamide m/z: 504.2 [M + 1] J-2

1-(6-(1H-imidazol-1- yl)pyridin-2-yl)-N- ((1R,2R,4S)-7-(4-methoxybenzyl)-7- azabicyclo[2.2.1]heptan-2- yl)-1H-indazole-5-carboxamide J-3

N-((1R,2R,4S)-7-(4- methoxybenzyl)-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-phenylpyridin-2- yl)-1H-indazole-5- carboxamide J-4

1-(6-(1H-pyrazo1-1- yl)pyridin-2-yl)-N- ((1R,2R,4S)-7-(4-methoxybenzyl)-7- azabicyclo[2.2.1]heptan-2- yl)-1H-indazole-5-carboxamide J-5

1-(6-cyclopropylpyridin-2-yl)- N-((1R,2R,4S)-7-(4- methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)- 4,5,6,7-tetrahydro-1H-indazole-5-catboxamide and 2- (6-cyclopropylpyridin-2-yl)-N-((1R,2R,4S)-7-(4- methoxybenzyl)-7- azabicyclo[2.2.1]heptan-2-yl)-4,5,6,7-tetraltydro-2H- indazole-5-catboxamide m/z: 498.2 [M + 1] and

J-6

1-(6-(1,1- difluoroethyl)pyridin-2-yl)-N- ((1R,2R,4S)-7-(4-methoxybenzyl)-7- azabicyclo[2.2.1]heptan-2-yl)-1H-indazole-5-carboxamide m/z: 518.0 [M + 1] J-7

1-(6-(difluoromethoxy)pyridin- 2-yl)-N-((1R,2R,4S)-7-(4-methoxybenzyl)-7- azabicyclo[2.2.1]heptan-2-yl)-1H-indazole-5-carboxamide m/z: 520.0 [M + 1] J-8

1-(6-(difluoromethyl)pyridin- 2-yl)-N-((1R,2R,4S)-7-(4-methoxybenzyl)-7- azabicyclo[2.2.1]heptan-2-yl)-1H-indazole-5-carboxamide m/z: 504.0 [M + 1] J-9

1-([2,2′-bipyridin]-6-yl)-N- ((1R,2R,4S)-7-(4- methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)- 1H-indazole-5-carboxamide m/z: 531.2 [M +1] J-10

1-(6-(1,1- difluoroethyl)pyridin-2-yl)-N- ((1R,2R,4S)-7-(4-methoxybenzyl)-7- azabicyclo[2.2.1]heptan-2-yl)- 4,5,6,7-tetrahydro-1H-indazole-5-carboxamide and 2- (6-(1,1-difluoroethyl)pyridin-2-yl)-N-((1R,2R,4S)-7-(4- methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)- 4,5,6,7-tetrahydro-2H-indazole-5-carboxamide and

J-11

1-(6-(difluoromethoxy)pyridin- 2-yl)-N-((1R,2R,4S)-7-(4-methoxybenzyl)-7- azabicyclo[2.2.1]heptan-2-yl)- 4,5,6,7-tetrahydro-1H-indazole-5-carboxamide and 2- (6-(difluoromethoxy)pyridin-2-yl)-N-((1R,2R,4S)-7-(4- methoxybenzyl)-7- azabicyclo[2.2.1]heptan-2-yl)-4,5,6,7-tetrahydro-2H- indazole-5-carboxamide and

J-12

1-(6-(1- cyanocyclopropyl)pyridin-2- yl)-N-((1R,2R,4S)-7-(4-methoxybenzyl)-7- azabicyclo[2.2.1]heptan-2-yl)- 4,5,6,7-tetrahydro-1H-indazole-5-carboxamide and 2- (6-(1- cyanocyclopropyl)pyridin-2-yl)-N-((1R,2R,4S)-7-(4- methoxybenzyl)-7- azabicyclo[2.2.1]heptan-2-yl)-4,5,6,7-tetrahydro-2H- indazole-5-carboxamide and

Intermediate K: 3-(4-methylpyrimidin-2-yl)-1H-indole-6-carboxylic acid

Step 1: A glass microwave reaction vessel was charged with methyl3-bromo-1H-indole-6-carboxylate (0.15 g, 0.590 mmol),1,3,2-dioxaborolane (0.225 g, 0.886 mmol) and[1,1-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complexwith dichloromethane (0.072 g, 0.089 mmol) in potassium acetate (0.098g, 1.004 mmol) and THF (3 ml). The reaction mixture was stirred andheated in a microwave reactor at 120° C. for 20 min. LCMS showed fullconversion. The reaction mixture was diluted with water and extractedwith DCM. The organic extract was concentrated in vacuo to give thecrude material as a daric brown oil which was used for next stepdirectly.

Step 2: A glass microwave reaction vessel was charged with methyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate(crude product from step 1), 2-chloro-4-methylpyrimidine (0.091 g, 0.708mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]pd(ii)me-t-butylether (0.087 g, 0.118 mmol) in THF (2.95 ml) followed by K3PO4(1N) (1.2 ml, 1.2 mmol). The reaction mixture was purged with N₂,stirred and heated in a microwave reactor at 120° C. for 6 min. LCMSshowed desired product. The organic extract was diluted with water andextracted with DCM. The organic phase was washed with water andconcentrated. The solution was filtered and concentrated in vacuo togive the crude material as an orange oil. The crude material wasabsorbed onto a plug of silica gel and purified by chromatographythrough a 10 g biotage ultra column, eluting with a gradient of 10% to60% EtOAc/EtOH (3/1) in Heptane, to provide methyl3-(4-methylpyrimidin-2-yl)-1H-indole-6-carboxylate (0.06 g, 0.224 mmol,38% yield) as orange foam. m/z: 268.2 [M+1]

Step 3: Refer to intermediate E step 2 to provide3-(4-methylpyrimidin-2-yl)-1H-indole-6-carboxylic acid (0.025 g, 0.1mmol, 42.2% yield). m/z: 254.2 [M+1]

The intermediates in the table below were made by identical procedures:

Int. Structure Name LC/MS data K-1

6-(4-methylpyrimidin-2-yl)-1H-indole-2-carboxylic acid m/z: 254.2 [M +1]

Intermediate L:

Step 1:

A glass microwave reaction vessel was charged with6-methyl-2-pyridylzinc bromide (0.5M) (1.19 ml, 0.595 mmol), methyl3-bromo-1-methyl-1h-indazole-6-carboxylate (0.1 g, 0.372 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]pd(ii)Me-tert-butylether (0.041 g, 0.056 mmol) in THF (0.74 ml). The reactionmixture was stirred and heated in a microwave reactor at 100° C. for 5min. LC/MS showed full conversion to desired product. The reactionmixture was diluted with water and extracted with DCM. It wasconcentrated and used for next step directly m/z: 282.2 [M+1]

Step 2:

Refer to intermediate E step 2 to provide1-methyl-3-(6-methylpyridin-2-yl)-1H-indazole-6-carboxylic acid (0.12 g,0.449 mmol, 121% yield) as off-white solid. m/z: 268.2 [M+1]

The intermediates in the table below were made by identical procedures:

Int. Structure Name LC/MS data L-1

5-chloro-1-methyl-3-(6-methytpyridin-2- yl)-1H-indazole-6-carboxylicacid m/z: 302.0 [M + 1] L-2

methyl 3-(6-methylpyridin-2-yl-1H- indazole-6-carboxylate m/z: 268.1[M + 1]

Intermediate M:4-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-propoxybenzamide

Step 1:

To a reaction vial was added, 1-bromopropane (0.149 g, 1.212 mmol),cesium carbonate (0.282 g, 0.866 mmol), methyl 4-bromo-3-hydroxybenzoate(0.200 g, 0.866 mmol), and N,N-dimethylformamide (2.164 ml). The vialwas capped and heated to 50° C. for 1 hour. The reaction was complete asdetermined by LCMS. The reaction was diluted with DCM (10 mL) andfiltered. The filtrate was removed in vacuo and the remaining crudematerial was used directly in the next step, m/z: 274.8 [M+1]

Step 2:

The crude material from Step 1, was take up in EtOH (5 mL). To this,NaOH (1M) (2.0 ml, 2.0 mmol) was added and the reaction stirred at 50°C. for 1 hour. The solvent was removed in vacuo and the remaining crudematerial was taken up in 5 mL of water. The solution was acidified with1N HCl aq. slowly until pH˜2. The resulting white solid was filtered anddried in vacuo, to give 4-bromo-3-propoxybenzoic acid (0.186 g, 0.718mmol, 83% yield). m/z: 256.0 [M−1]

Step 3:

To a red cap vial containing 4-bromo-3-propoxybenzoic acid (0.149 g,0.576 mmol) and oxalyl chloride (0.101 ml, 1.152 mmol) in DCM (2.88 ml)was added 3 drops of DMF. The reaction was stirred for 30 minutes andthen concentrated under reduced pressure and dried on the high vacuum.The crude material was used directly in the next step.

Step 4:

To red cap vial containing 4-bromo-3-propoxybenzoyl chloride and(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonitrilehydrochloride (Intermediate A, Peak 1 derived) (0.100 g, 0.576 mmol) inDCM (2.88 ml) followed by triethylamine (0.401 ml, 2.88 mmol) at 0 C. Itwas stirred at rt for 1 hour. LCMS confirms reaction complete. Thereaction mixture was diluted with water and extracted with DCM. It wasconcentrated and the crude material was absorbed onto a plug of silicagel and purified by chromatography through a 10 g biotage ultra, elutingwith a gradient of 0% to 75% EtOAc in Heptane, to provide4-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-propoxybenzamide(0.156 g, 0.412 mmol, 71.6% yield) as off-white solid, m/z: 379.8 [M+1]

The intermediates in the table below were made by identical procedures:

Int. Structure Name LC/MS data M-1

4-bromo-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-ethoxybenzamide m/z: 365.0 [M + 1] M-2

4-bromo-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(cyclopropylmethoxy)benzamide m/z: 391.0 [M + 1] M-3

4-bromo-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylbutoxy)benzamide m/z: 406.0 [M + 1] M-4

4-bromo-2-chloro-N- ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5- isobutoxybenzamide m/z: 428.0 [M + 1]M-5

4-bromo-3-butoxy-N- ((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)benzamide m/z: 393.2 [M + 1] M-6

4-bromo-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(cyclobutylmethoxy)benzamide m/z: 405.2 [M + 1]

Intermediate N:4-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-isopropoxybenzamide

Step 1:

To a reaction vial was added, methyl 4-bromo-3-hydroxybenzoate (0.200 g,0.866 mmol), triphenylphosphine (0.386 g, 1.472 mmol), propan-2-ol(0.073 g, 1.212 mmol), and tetrahydrofuran (2.164 ml). The reaction vialwas cooled to 0° C. and diisopropyl azodicarboxylate (0.290 ml, 1.472mmol) was added. The ice bath was removed and the reaction allowed towarm up to room temperature. After 3 hours, the reaction was complete asdetermined by LCMS. The reaction was quenched with water and extractedwith DCM. The organics were dried over MgSO₄ and filtered. The solventwas removed in vaccuo and the erode material was absorbed onto a plug ofsilica gel and purified by chromatography through a 10 g biotage ultracolumn, eluting with a gradient of 10% to 60% EtOAc/Heptane, to providemethyl 4-bromo-3-isopropoxybenzoate (0.189 g, 0.692 mmol, 80% yield),m/z: 274.0 [M+1]

Step 2, Step 3, and Step 4:

Refer to intermediate M step 2, step 3, and step 4 to provide4-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-isopropoxybenzamide(derived from peak 1 azanorbornane) (0.123 g, 0.325 mmol, 56.5% yield),m/z: 379.0 [M+1]

Intermediate O:1-(cyclopropylmethyl)-3-(6-methylpyridin-2-yl)-1H-indazole-6-carboxylicacid

To a ted cap vial containing Intermediate L-2 (0.12 g, 0.449 mmol) intetrahydrofuran (1.7% ml) was added NaH (60%) (0.032 g, 0.808 mmol).This was stirred at rt for 5 min then (bromomethyl)cyclopropane (0.085g, 0.629 mmol) was added. The reaction mixture was stirred at it for 3 hwhen LC/MS showed no conversion. Additional 30 mg of NaH. was addedfollowed by 3 equiv. of (bromomethyl)cyclopropane and the reaction washeated to 70° C. for 1 hour to provide the desired product. Afterquenching with water a precipitate formed which was filtered to providethe acid which was used erode for amidation. m/z: 308.2 [M+1],Alternatively, potassium tert-butoxide could also be used as base toprovide better conversion with other electrophiles.

The intermediates in the table below were made by identical procedures:

Int. Structure Name LC/MS data O-1

1-isobutyl-3-(6-methylpyridin-2-yl)-1H- indazole-6-carboxylic acid m/z:310.2 [M + 1] O-2

3-(6-methylpyridin-2-yl)-1-(4,4,4-triflurobutyl)-1H-indazole-6-carboxylic acid m/z: 364.2 [M + 1] O-3

3-(6-methylpyridin-2-yl)-1-propyl-1H- indazole-6-carboxylic acid m/z:296.2 [M + 1]

Intermediate P:3-(3,5-dichlorophenyl)-3-azabicyclo[4.1.0]heptane-7-carboxylic acid

Step 1: A solution of ethyl 3-azabicyclo[4.1.0]heptane-7-carboxylatehydrochloride (0.250 g, 1.215 mmol), 1,3-dichloro-5-iodobenzene (0.398g, 1.459 mmol), cesium carbonate (0.990 g, 0.3.04 mmol), xantphos (0.070g, 0.122 mmol) in 1,4-dioxane (10 mL) was added Pd₂(dba)₃ (0.056 g,0.061 mmol). The reaction mixture was heated at 85° C. for 16 h beforeit was Filtered through a celite pad and washed with ethyl acetate (20mL). The filtrate was evaporated under vacuum and purified by columnchromatography using 10% to 12% ethyl acetate in petroleum ether toprovide ethyl3-(3,5-dichlorophenyl)-3-azabicyclo[4.1.0]heptane-7-carboxylate (0.200g, 0.637 mmol, 52.4% yield) as light-yellow solid. ¹H NMR (400 MHz,Chloroform-d): δ ppm 6.75 (t, J=1.7 Hz, 1H), 6.62 (d, J=1.8 Hz, 2H),4.15 (q, J=7.1 Hz, 2H), 3.64 (d, J=12.6 Hz, 1H), 3.46-3.51 (m, 1H),3.17-3.23 (m, 1H), 3.02 (m, 1H), 2.10-2.25 (m, 1H), 1.95-2.06 (m, 1H),1.77-1.88 (m, 2H), 1.66 (t, J=4.2 Hz, 1H), 1.28 (t, J=7.1 Hz, 3H); m/z(ESI): 314.0 (M+H)⁺.

Step-2: To a solution of ethyl3-(3,5-dichlorophenyl)-3-azabicyclo[4.1.0]heptane-7-carboxylate (0.200g, 0.637 mmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (1mL) was added Lithium Hydroxide mono hydrate (0.080 g, 1.910 mmol) andthe reaction mixture was stirred for 16 h. The solvents were evaporatedunder vacuum and the reaction mixture w as neutralized with 1.5N HCl (2mL). The precipitated solid was filtered and washed with water (1 mL) toget 3-(3,5-dichlorophenyl)-3-azabicyclo[4.1.0]heptane-7-carboxylic acid(0.075 g, 41.2% yield). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 12.12 (s, 1H),6.80 (s, 2H), 6.76 (s, 1H), 3.47-3.64 (m, 2H), 3.03-3.29 (m, 2H),1.94-2.12 (m, 1H), 1.84 (m, 1H), 1.54-1.71 (m, 2H), 1.46 (t, J=4.1 Hz,1H); m/z (ESI): 288.2 (M−H)⁺.

The intermediates in the table below were made following similarprocedures:

Int. Structure Name ¹H NMR MS Data P-1

1-(6-(1- cyanocyclopropyl) pyridin-2- yl)piperidine-3- carboxylic acidm/z (ESI): 272.2 (M + H)⁺ P-2

1-(6- cyclopropylpyridin- 2-yl)piperidine- 4-carboxylic acid ¹H NMR (400MHz, DMSO-d₆): δ ppm 7.72 (t, J = 8.1 Hz, 1 H), 6.97 (d, J = 9.0 Hz, 1H), 6.47 (d, J = 7.5 Hz, 1 H), 4.15 (dt, J = 13.4, 4.1 Hz, 2 H),3.09-3.25 (m, 2H), 2,60 (m, 1 H), 2.39 (m, 1 H), 1.83-2.00 (m, 2 H),1.51-1.68 (m, 2 H), 1.08 (m, 2 H), 0.74−0.97 (m, 2 H). m/z (ESI): 247.3(M + H)⁺ P-3

1-(6-(1- cyanocyclopropyl) pyridin-2- yl)pyrrolidine-3- carboxylic acidm/z (ESI): 258.3 (M + H)⁺

Intermediate Q: 6-(3-(1-cyanocyclopropyl)phenyl)nicotinic acid

Step 1: A solution of methyl 6-bromonicotinate (1.5 g, 6.94 mmol),(3-(1-cyanocyclopropyl)phenyl)boronic acid (1.948 g, 10.42 mmol) andpotassium acetate (2.044 g, 20.83 mmol) in 1,4-dioxane (20.0 mL) wasadded Pd(dppf)Cl₂ (0.508 g, 0.694 mmol). The reaction mixture wasstirred at 80° C. for 16 h before it was diluted with water andextracted with EtOAc (3×150 mL). The organic extracts were dried overNa₂SO₄, filtered and concentrated in vacuo. The concentrate was purifiedby column chromatography using a gradient of 0% to 20% EtOAc in petether, to provide methyl 6-(3-(1-cyanocyclopropyl)phenyl)nicotinate (1.2g, 4.31 mmol, 62.1% yield) as while solid.

¹H NMR (400 MHz, DMSO-d₆): δ ppm 9.12-9.22 (m, 1H), 8.38 (dd, J=8.4, 2.2Hz, 1H), 8.21 (dd, J=8.4, 0.9 Hz, 1H), 8.01-8.21 (m, 2H), 7.57 (td,J=7.7, 0.8 Hz, 1H), 7.45-7.55 (m, 1H), 7.34-7.49 (m, 1H), 3.92 (s, 3H),1.74-1.89 (m, 4H); m/z (ESI): 279.3 (M+H)⁺.

Step-2: To a solution of methyl6-(3-(1-cyanocyclopropyl)phenyl)nicotinate (12 g, 4.31 mmol) intetrahydrofuran (3 mL) and water (1 mL) was added Lithium Hydroxide monohydrate (0.516 g, 21.56 mmol) and the reaction mixture was stirred for16 h. The solvents were evaporated under vacuum and the reaction mixturewas neutralized with 1.5N HCl (2 mL). The precipitated solid wasfiltered and washed with water (1 mL) to obtain6-(3-(1-cyanocyclopropyl)phenyl)nicotinic acid (1 g, 3.78 mmol, 88%yield). ¹H NMR (400 MHz, DMSO-d₆): δ ppm 9.17 (d, J=2.2 Hz, 1H), 8.35(dd, J=8.3, 2.3 Hz, 1H), 8.17 (d, J=8.3 Hz, 1H), 8.01-8.15 (m, 2H), 7.56(t, J=7.7 Hz, 1H), 7.47 (d, J=7.9 Hz, 1H), 1.82 (m, 2H), 1.63 (m, 2H);m/z (ESI): 265.1 (M+H)⁺.

The intermediates in the table below were made following similarprocedures:

Int. Structure Name ¹H NMR MS data Q-1

3-chloro-3′- cyclopropyl- 5′-fluoro-[1,1′- biphenyl]-4- carboxylic acid¹H NMR (400 MHz, DMSO-d₆): δ ppm 13.44 (s, 1 H), 7.90 (d, J = 1.8 Hz, 1H), 7.86 (s, 1 H), 7.77 (dd, J = 8.2, 1.8 Hz, 1 H), 7.34-7.42 (m, 1 H),7.30-7.37 (m, 1 H), 6.97 (dt, J = 10.1, 1.9 Hz, 1 H), 2.04 (m, 1 H),0.95-1.06 (m, 2 H), 0.78- 0.95 (m, 2 H). m/z (ESI): 289.1 (M − H)⁺ Q-2

6-(1- cyanocyclopropyl)- [2,3′- bipyridine]-6′- carboxylic acid ¹H NMR(400 MHz, DMSO-d₆): δ ppm 9.36 (d, J = 2.3 Hz, 1 H), 8.60 (dd, J = 8.2,2.3 Hz, 1 H), 8.15 (d, J = 8.2 Hz, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 8.02(t, J = 7.8 Hz, 1 H), 7.63 (d, J = 7.7 Hz, 1 H), 1.88 (t, J = 3.3 Hz, 4H). m/z (ESI): 266.1 (M + H)⁺ Q-3

2-chloro-4-(6-(1- ethynylcyclopropyl) pyridin- 2-yl)benzoic acid ¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.14 (d, J = 1.7 Hz, 1 H), 8.06 (dd, J = 8.1,1.7 Hz, 1 H), 7.91 (d, J = 4.4 Hz, 2 H), 7.78-7.87 (m, 2 H), 3.26 (br s,1 H), 1.70 (m, 2 H), 1.46 (m, 2 H). m/z (ESI): 298.1 (M + H)⁺ Q-4

2-chloro-4-(3- cyano-3- methyl-2,3- dihydro-1H- inden-5- yl)benzoic acid¹H NMR (400 MHz, DMSO-d₆): δ ppm 13.40 (s, 1 H), 7.87-7.93 (m, 3 H),7.78 (dd, J = 8.1, 1.9 Hz, 1 H), 7.72 (dd, J = 7.9, 1.8 Hz, 1 H), 7,45(d, J = 7.9 Hz, 1 H), 3.05 (t, J = 7.1 Hz, 2 H), 2.58-2.67 (m, 1 H),2.23 (dt, J = 13.0, 7.5 Hz, 1 H), 1.72 (s, 3 H). m/z (ESI): 310.0 (M +H)⁺ Q-5

4-(6-tert- butyl)pyridin- 2-yl)-2- chlorobenzoic acid ¹H NMR (400 MHz,DMSO-d₆): δ ppm 13.46 (s, 1 H), 8.27 (d, J = 1.7 Hz, 1H), 1 H), 8.17(dd, J = 8.1, 1.8 Hz, 1 H), 7.88-7.98 (m, 2 H), 7.87 (t, J = 7.7 Hz, 1H), 7.50 (dd, J = 7.6, 1.1 Hz, 1 H), 1.39 (s, 9 H). m/z (ESI): 290.1(M + H)⁺ Q-6

2-chloro-4-(6- (2- cyanopropan- 2-yl)pyrazin- 2-yl)benzoic acid m/z(ESI): 302.1 (M + H)⁺ Q-7

2-chloro-4-(6-(1- cyanocyclobutyl) pyridin-2- yl)benzoic acid m/z (ESI):313.1 (M + H)⁺ Q-8

2-chloro-4-(6- (1-cyano-3,3- difluorocyclobutyl) pyridin-2- yl)benzoicacid ¹H NMR (400 MHz, DMSO-d₆), δ ppm 13.54 (s, 1 H), 8.31 (d, J = 1.8Hz, 1 H), 8.19 (td, J = 7.8, 7.3, 1.3 Hz, 2 H), 8.10 (t, J = 7.8 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.75 (dd, J = 7.7, 0.8 Hz, 1 H). 3.51-3.71(m, 4 H). m/z (ESI): 348.9 (M)⁺ Q-9

2-chloro-3′-(1- cyanocyclopropyl)- [1,1-biphenyl]-3- carboxylic acid ¹HNMR (400 MHz, DMSO-d₆): δ ppm 7.68 (dd, J = 5.9, 3.7 Hz, 1 H), 7.50 (m,3 H), 7.27-7.40 (m, 3 H), 1.77 (m, 2 H), 1.54 (m, 2 H). m/z (ESI): 296.1(M − H)⁻ Q-10

2-chloro-4-(6- cyclopropylpydin- 2-yl)benzoic acid ¹H NMR (400 MHz,DMSO-d₆): δ ppm 13.46 (s, 1H), 8.18 (d, J = 1.7 Hz, 1 H), 8.09 (dd, J =8.2, 1.7 Hz, 1 H), 7.90 (d, J = 8.1 Hz, 1 H), 7.84 (dd, J = 7.9, 1.1 Hz,1 H), 7.78 (t, J = 7.7 Hz, 1 H), 7.35 (dd, J = 7.6, 1.0 Hz, 1 H), 2.19(m, 1 H), 0.98- 1.07 (m, 4 H). Q-11

3-chloro-3′-(1- cyanocyclopropyl)- 5′-fluoro- [1,1′- biphenyl]-4-carboxylic acid ¹H NMR (400 MHz, DMSO-d₆): δ ppm 13.48 (s, 1H), 7.95 (d,J = 1.7 Hz, 1 H), 7.89 (d, J = 8.1 Hz, 1 H), 7.80 (dd, J = 8.2, 1.8 Hz,1 H), 7.57-7.66 (m, 1 H), 7.48 (t, J = 1.6 Hz, 1H); 7.28 (dt, J = 9.8,2.0 Hz, 1 H); 1.79-1.89 (m, 2 H), 1.65- 1.79 (m, 2H). m/z (ESI): 314.1(M + H)⁺ Q-12

4-(6-(1- cyanocyclopropyl) pyridin-2- yl)-2- cyclopropylbenzoic acid ¹HNMR (400 MHz, Chloroform-d): δ ppm 8.08 (d, J = 8.2 Hz, 1 H) 7.79- 7.86(m, 2 H), 7.69-7.83 (m, 1 H), 7.63-7.69 (m, 2 H), 2.87 (m, 1 H), 1.97(m, 2 H), 1.80 (m, 2 H), 1.04- 1.17 (m, 2 H), 1.27 (m, 2 H), 1.09 (m, 2H) m/z (ESI): 305.2 (M + H)⁺

Intermediate R: 1-cyclopentyl-1H-indazole-3-carboxylic acid

Step 1: To a solution of methyl 1H-indazole-3-carboxylate (1.0 g, 5.68mmol) in N,N-dimethylformamide (10.0 mL) were added cesium carbonate(4.07 g, 12.49 mmol) and bromocyclopentane (0.931 g, 6.24 mmol). Thereaction mixture was stirred at 90° C. for 16 h before it was dilutedwith ice water (2×100 mL) and extracted with ethyl acetate (100 mL). Theorganic extracts were dried over Na₂SO₄, filtered and concentrated invacuo. The concentrate was purified by column chromatography using agradient of 0% to 15% ethyl acetate in pet ether, to provide methyl1-cyclopentyl-1H-indazole-3-carboxylate (0.7 g, 2.87 mmol, 50.5% yield)as a light brown oil. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 8.09 (dt, J=8.1,1.1 Hz, 1H), 7.87 (dt, J=8.6, 1.0 Hz, 1H), 7.48-7.52 (m, 1H), 7.33-7.38(m, 1H), 5.26-5.36 (m, 1H), 3.92 (s, 3H), 2.18 (m, 2H), 2.02-2.08 (m,2H), 1.90 (m, 2H), 1.68-1.78 (m, 2H); m/z (ESI): 245.2 (M+H)+.

Step 2: To a solution of methyl 1-cyclopentyl-1H-indazole-3-carboxylate(0.7 g, 2.87 mmol) in tetrahydrofuran (1 mL), methanol (1 mL) and water(1 mL) was added lithium hydroxide mono hydrate (0.274 g, 11.46 mmol)and the reaction mixture was stirred for 16 h. The solvents wereevaporated under vacuum and the reaction mixture was neutralized with1.5 N HCl. The precipitated solid was filtered and washed with water (1mL) to get 1-cyclopentyl-1H-indazole-3-carboxylic acid (0.6 g, 2.61mmol, 91% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 12.97(s, 1H), 8.08 (dd, J=8.2, 1.2 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.47 (m,1H), 7.29-7.34 (m, 1H), 5.24-5.32 (m, 1H), 2.15-2.22 (m, 2H), 2.05 (m,2H), 1.90 (m, 2H), 1.73 (m, 2H); m/z (ESI): 231.3 (M+H)⁺.

The intermediates in the table below were made following similarprocedures:

Int. Structure Name 1H NMR MS Data R-1

1-(3,5- dichlorobenzyl) azetidine-2- carboxylic acid ¹H NMR (400 MHz,DMSO-d₆): δ ppm 7.47 (t, J = 2.0 Hz, 1H), 7.36 (d, J = 2.0 Hz, 2 H),3.87 (d, J = 13.9 Hz, 1 H), 3.72 (t, J = 8.5 Hz, 1 H), 3.56 (d, J = 3.9Hz, 1 H), 3.19 (td, J = 7.2, 3.3 Hz, 1 H), 2.89 (td, J = 8.5, 6.7 Hz, 1H), 2.06-2.23 (m, 2 H). m/z (ESI): 260.0 (M + H)⁺ R-2

1-(3,5- dichlorobenzyl) pyrrolidine- 3-carboxylic acid m/z (ESI): 274.1(M + H)⁺

Intermediate S: 2-chloro-4-((1-cyanocyclopropyl)methoxy)benzoic acid

Step 1: To a solution of methyl 2-chloro-3-hydroxybenzoate (1.0 g, 5.36mmol), 1-(hydroxymethyl)cyclopropyl-1-carbonitrile (0.5% g, 5.36 mmol),triphenylphosphine (2.81 g, 10.72 mmol) in THF (10 mL) was added DIAD(2.084 mL, 10.72 mmol) at 0° C. The reaction mixture was stirred atambient temperature for 16 h before it was diluted with water (30 mL)and extracted with EtOAc (2×30 mL). The organic extracts were washedwith brine, dried over Na₂SO₄, filtered and concentrated in vacuo. Theconcentrate was purified by column chromatography using 0% to 30% EtOAcin petroleum ether, to provide methyl2-chloro-3-((1-cyanocyclopropyl)methoxy)benzoate (1.5 g, 5.65 mmol, 105%yield) as light-yellow sticky liquid, m/z (ESI): 264.9 (M−H)⁻.

Step 2: To a solution of methyl2-chloro-3-((1-cyanocyclopropyl)methoxy)benzoate (1.5 g, 5.65 mmol) intetrahydrofuran (10 mL), methanol (2 mL) and water (5 mL) was addedLithium Hydroxide mono hydrate (0.811 g, 33.9 mmol) and the reactionmixture was stirred for 16 h. The solvents were evaporated under vacuumand the reaction mixture was neutralized with 1.5 N HCl. Theprecipitated solid was filtered and washed with water (1 mL) to get2-chloro-4-((1-cyanocyclopropyl)methoxy)benzoic acid (0.9 g, 3.58 mmol,63.3% yield) as light-yellow oil. m/z (ESI): 249.1 (M−H)⁺.

The intermediates in the table below were made following similarprocedures:

Int. Structure Name 1H NMR MS Data S-1

2-chloro-3-(3- cyanocyclobtaoxy) benzoic acid m/z (ESI): 252.1 (M − H)⁺S-2

2-chloro-4-(3- cyanocyclobtaoxy) benzoic acid ¹H NMR(400 MHz, DMSO- d₆):δ ppm 13.1 (s, 1 H), 7.87- 7.78 (m, 1 H), 7.02 (d, J = 2.5 Hz, 1 H),7.00-6.89 (m, 1 H), 5.15-5.04 (m, 1 H), 3.46 (m, 1 H), 2.89-2.78 (m, 2H), 2.51- 2.43 (m, 2 H). m/z (ESI): 250.1 (M − H)⁺

Intermediate T: 2-chloro-4-(3-cyanopiperidin-1-yl)benzoic acid

Step 1: To a mixture of methyl 2-chloro-4-fluorobenzoate (1.0 g, 5.30mmol) and piperidine-3-carbonitrile (0.584 g, 5.30 mmol) inA-methyl-2-pyrrolidinone (10 mL) was added K₂CO₃ (0.733 g, 5.30 mmol)and the reaction mixture was heated at 135° C. for 16 h. The reactionmixture was quenched with ice cubes and stirred for 5 min to get solid.The solid was filtered and washed with water and dried under suction toget methyl 2-chloro-4-(3-cyanopiperidin-1-yl)benzoate (0.85 g, 57.5%Yield). ¹H NMR (400 MHz, Chloroform-d): δ ppm 7.87 (d, J=8.9 Hz, 1H),6.91 (d, J=2.6 Hz, 1H), 6.79 (dd, J=8.9, 2.6 Hz, 1H), 3.92 (s, 3H), 3.69(ddt, J=12.9, 3.6, 1.3 Hz, 2H), 3.37-3.51 (m, 2H), 3.26 (ddd, J=12.7,8.8, 3.3 Hz, 2H), 2.79-2.92 (m, 2H), 2.40 (t, J=8.1 Hz, 1H), m/z (ESI):279.1 (M+H)⁺.

Step 2: To a solution of methyl2-chloro-4-(3-cyanopiperidin-1-yl)benzoate (0.850 g, 3.05 mmol) in amixture tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL) wasadded lithium hydroxide mono hydrate (0.384 g, 9.15 mmol) at rt whichwas stirred for 16 h. The solvent was evaporated under vacuum andneutralized with 1.5 N HCl to obtain a solid that was washed with waterand dried under suction to provide2-chloro-4-(3-cyanopiperidin-1-yl)benzoic acid (0.60 g, 74.3% yield). ¹HNMR (400 MHz, DMSO-d₆): δ ppm 7.70-7.80 (m, 1H), 7.03 (d, J=2.6 Hz, 1H),6.97 (dd, J=8.9, 2.6 Hz, 1H), 3.58-3.74 (m, 2H), 3.30-3.50 (m, 2H),3.02-3.18 (m, 1H), 1.80-2.06 (m, 2H), 1.54-1.74 (m, 2H) m/z (ESI): 265.1(M+H)⁺.

The intermediates in the table below were made following similarprocedures:

Int. Structure Name 1H NMR MS Data T-1

1-(3-cyanophenyl)-1H- indazole-3-carboxylic acid ¹H NMR(400 MHz,DMSO-d₆): δ ppm 13.45 (s, 1 H), 8.16-8.30 (m, 2H), 7.95- 8.16 (m, 2 H),7.70-7.95 (m, 1 H), 7.55-7.66 (m, 1 H), 7.42- 7.51 (m, 1 H), 7.12-7.36(m, 1 H). m/z (ESI): 264.1 (M + H)⁺ T-2

2-chloro-4-(2-cyano-6- azabicyclo[3.2.1]octan-6- yl)berizoic acid ¹HNMR(400 MHz, DMSO- d₆): δ ppm 12.36 (br s, 1 H), 7.72- 7.80 (m, 1 H),6.56-6.70 (m, 2 H), 3.22-3.35 (m, 4 H), 2.18 (t, J = 8.1 Hz, 3 H),1.90-2.02 (m, 4 H). m/z (ESI): 291.1 (M + H)⁺ T-3

2-chloro-4-(3- (cyanomethyl)pyrrolidin-1- yl)benzoic acid ¹H NMR (400MHz, DMSO- d₆): δ ppm 7.76 (d, J = 8.6 Hz, 1 H), 6.41-6.59 (m, 2 H),3.50 (dd, J = 10.2, 7.0 Hz, 1 H), 3.37- 3.45 (m, 1 H), 3.27-3.34 (m, 1H), 3.03 (dd, J = 10.2, 6.7 Hz, 1 H), 2.64-2.77 (m, 2 H), 2.59- 2.64 (m,1 H), 2.15-2.22 (m, 1 m/z (ESI): 265.1 (M + H)⁺ H), 1.77-1.88 (m, 1 H).T-4

2-chloro-4-(3- (cyanomethyl)piperidin-1- yl)benzoic acid ¹H NMR (400MHz, DMSO- d₆): δ ppm 12.57, (s, 1 H), 7.73 (d, J = 8.9 Hz, 1 H),6.61-7.06 (m, 2 H), 3.76 (t, J = 15.5 Hz, 2 H), 2.84 (ddd, J = 13.2,11.4, 3.0 Hz, 1 H), 2.70 (dd, J = 12.9, 10.1 Hz, 3 H), 1.78- 1.92 (m, 2H), 1.61-1.77 (m, 1 m/z (ESI): 279.1 (M + H)⁺ H), 1.33-1.56 (m, 1 H),1.15- 1.39 (m, 1 H). T-5

2-chloro-4-(4,5,6,7- tetrahydro-1H-indazol-1- yl)benzoic acid m/z (ESI):277.1 (M + H)⁺ T-6

2-chloro-4-(5,6- dihydrocyclopenta[c]pyrazol- 1(4H)-yl)benzoic acid ¹HNMR (400 MHz, DMSO- d₆): δ ppm 8.24 (d, J = 1.2 Hz, 1 H), 7.82-7.93 (m,2 H), 7.72- 7.82 (m, 1 H), 2.59-2.73 (m, 4 H), 2.31-2.51 (m, 2 H). m/z(ESI): 263.1 (M + H)⁺ T-7

2-chloro-4-(5,6- dihydrocyclopenta[c]pyrazol- 2(4H)-yl)benzoic acid ¹HNMR (400 MHz, DMSO- d₆): δ ppm 8.26 (d, J = 1.2 Hz, 1 H), 7.93 (d, J =2.1 Hz, 1 H), 7.91 (d, J = 8.6 Hz, 1 H), 7.81 (dd, J = 8.6, 2.2 Hz, 1H), 2.60-2.76 (m, 4 H), 2.32-2.42 (m, 2 H). S-8

1-(3-cyanophenyl)-1H- pyrazole-3-carboxylic acid m/z (ESI): 214.1 (M +H)⁺

Intermediate U: 1-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3-carboxylicacid

Step 1: To a mixture of methyl 4H-1,2,4-triazole-3-carboxylate (0.599 g,4.72 mmol) and (3,5-dichlorophenyl)boronic acid (0.9 g, 4.72 mmol) indichloromethane (9 mL) was added pyridine (0.763 mL, 9.43 mmol) followedby copper (II) acetate (0.600 g, 3.30 mmol) and stirred rt for 16 hunder open air. The reaction mixture was filtered through a bed ofcelite and washed with EtOAc. The EtOAc layer was washed with water,brine, dried over Na₂SO₄, filtered and concentrated in vacuo to providethe crude material as a green oil. The crude material was absorbed ontoa plug of silica gel and purified by flash column chromatography elutingwith a gradient of 0% to 5% EtOAc in petroleum ether to provide methyl1-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3-carboxylate (0.8 g, 2.94mmol, 62.3% yield) as grey solid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 9.55(s, 1H), 8.05 (d, J=1.8 Hz, 2H), 7.78 (t, J=1.8 Hz, 1H), 3.92 (s, 3H).

Step 2: To a solution of methyl1-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3-carboxylate (0.8 g, 2.94mmol) in tetrahydrofuran (8 mL), water (2 mL) was added LiOH (0.176 g,7.35 mmol) at rt and w as stirred for 4 h. The residual solvent wasevaporated under reduced pressure and then neutralized with 1.5 N HClsolution. It was extracted with ethyl acetate, dried over Na₂SO₄,concentrated in vacuo to give the product1-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3-carboxylic acid (0.6 g, 2.325mmol, 79% yield) as a off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ ppm13.74, (br s, 1H), 9.50 (s, 1H), 8.04 (d, J=1.8 Hz, 2H), 7.78 (s, 1H).

Intermediate V:1-(3,5-dichlorophenyl)-N-((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)azepane-4-carboxamide

Step 1: To a solution of(1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-amine (0.900g, 3.87 mmol) in N,N-dimethylformamide (20 mL) were added1-(tert-butoxycarbonyl)azepane-4-carboxylic acid (0.943 g, 3.87 mmol),DIPEA (1.353 mL, 7.75 mmol) followed by HATU (2.209 g, 5.81 mmol) at rtand was stirred for 16 h. The reaction mixture was diluted with waterand extracted with EtOAc. The organic extracts were washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo to give the crudematerial as a light-yellow oil. The crude product was purified byreverse-phase preparative HPLC (0.1% TFA in CH₃CN/H₂O, gradient 40% to45%) to provide tert-butyl4-(((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)azepane-1-carboxylate(0.500 g, 1.093 mmol, 28.2% yield) as a light-yellow oil. ¹H NMR (400MHz, DMSO-d₆): δ ppm 9.62 (s, 1H), 8.25 (s, 1H), 7.46 (d, J=8.1 Hz, 2H),7.03 (d, J=8.1 Hz, 2H), 4.62 (s, 1H), 4.26 (d, J=56.3 Hz, 2H), 3.94 (s,2H), 3.79 (s, 2H), 3.12-3.30 (m, 2H), 2.24 (s, 2H), 1.89-2.05 (m, 2H),1.62-1.86 (m, 6H), 1.40 (s, 12H). m/z (ESI): 458.4 (M+H)⁺.

Step 2: To a solution of tert-butyl4-(((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)azepane-1-carboxylate(0.500 g, 1.093 mmol) in 1,4-dioxane (5 mL) was added HCl in dioxane (1mL, 5.46 mmol) dropwise at rt and stirred for 4 h. The solvent wasevaporated under vacuum to get N-((1R,2R,4S)-7-(4-methoxybenzyl)-7azabicyclo[2.2.1]heptan-2-yl)azepane-4-carboxamide hydrochloride (0.500g, 116% yield) as crude which was directly used for the next stepwithout purification.

Step 3: To a solution ofN-((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)azepane-4-carboxamidehydrochloride (0.500 g, 1.269 mmol) in THF (5 mL) was added LHMDS (1.0 Msolution in THF, 2.54 mL, 2.54 mmol) dropwise at 0° C. and then stirredfor 30 min at rt. To it 1,3-dichloro-5-iodobenzene (0.346 g, 1.269mmol), Ruphos precatalyst (0.023 g, 0.032 mmol) followed by Ruphos(0.015 g, 0.032 mmol) was added and the reaction mixture was degassedwith nitrogen for 5 min. After heating at 70° C. for 16 h. the reactionmixture was diluted with water and extracted with EtOAc. The organicextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo to give the crude material as a light-yellow oil.The crude product was purified by reverse-phase preparative HPLC (0.1%TFA in CH₃CN/H₂O, gradient 65% to 70% over 30 min) to provide1-(3,5-dichlorophenyl)-N-((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)azepane-4-carboxamide(0.150 g, 0.164 mmol, 12.94% yield) as a light-yellow solid. ¹H NMR (400MHz, DMSO-d₆): δ ppm 7.73-7.81 (m, 1H), 7.12-7.31 (m, 4H), 6.81-6.90 (m,1H), 6.65 (dt, J=4.6, 1.7 Hz, 2H), 3.73 (s, 3H), 3.47-3.61 (m, 2H), 3.42(dd, J=4.1, 1.8 Hz, 3H), 3.06-3.21 (m, 3H), 2.59 (d, J=7.2 Hz, 2H), 2.20(d, J=6.0 Hz, 2H), 1.92 (d, J=38.7 Hz, 4H), 1.58 (p, J=4.0 Hz, 4H), 1.36(s, 2H). m/z (ESI): 502.1, 504.1 (M+1)⁺.

The intermediates in the table below were made following similarprocedures:

Inc. No. Structure Name 1H NMR MS Data U-1

(1S,5S)-2-(3,5-dichlorophenyl)-N- ((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[3.1.0]hexane-4- carboxamide m/z (ESI): 486.1, 488.1 (M +H)⁺.

Intermediate V:3-(3,5-dichlorophenyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

Step 1: A mixture of furan-2(5H)-one (3.0 g, 35.7 mmol) andV-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (10.34 g, 43.5mmol) in dichloromethane (30 mL) was cooled to 0° C. and was treatedwith TFA (0.591 mL, 7.67 mmol) drop wise. It was stirred for 16 h at it.The reaction mixture was quenched with saturated NaHCO₃ and extractedwith DCM. The organic extracts were washed with brine, dried over Na₂SO₄filtered and concentrated in vacuo to give the crude material as ayellow oil. The crude material was absorbed onto a plug of silica geland purified by flash column chromatography eluting with a gradient of30% to 40% Ethyl acetate in petroleum ether to provide5-benzylhexahydro-1H-furo[3,4-c]pyrrol-1-one (3.2 g, 14.73 mmol, 41.3%yield) as light-yellow oil. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 7.12-7.40(m, 5H), 4.43 (t, J=8.7 Hz, 1H), 3.87-4.09 (m, 1H), 3.56 (d, J=2.0 Hz,2H), 3.12 (ddd, J=9.5, 7.1, 1.2 Hz, 1H), 2.90-3.06 (m, 2H), 2.75-2.86(m, 1H), 2.33 (dt, J=9.1, 7.2 Hz, 2H). m/z (ESI): 218.2 (M+H)⁺.

Step 2: A mixture of 5-benzylhexahydro-1H-furo[3,4-c]pyrrol-1-one (5.0g, 23.01 mmol) and Boc-anhydride (8.01 mL, 34.5 mmol) in methanol (100mL) was purged with nitrogen for 2 min and then changed with Pd—C (1.225g, 0.050 mmol) at rt. The reaction mixture was heated at 65° C. under 50psi pressure of Hydrogen gas for 16 h. The reaction mixture was filteredthrough celite pad and washed with methanol. The filtrate was evaporatedto obtain crude material which was purified by silica gel chromatographyeluting with 25% to 30% Ethyl acetate in Petroleum ether to providetert-butyl-1-oxotetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-carboxylate (5.0g, 22.00 mmol, % % yield) as a light-yellow oil. ¹H NMR (400 MHz,Chloroform-d): δ ppm 4.47 (dd, J=9.6, 5.9 Hz, 1H), 4.22 (d, J=9.6 Hz,1H), 3.89 (d, J=11.5 Hz, 1H), 3.71-3.84 (m, 1H), 3.64 (s, 1H), 3.33 (s,1H), 3.16-3.26 (m, 2H), 1.48 (s, 9H).

Step 3: To a solution oftert-butyl-1-oxotetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-carboxylate (5.0g, 22.00 mmol) in 1,4-dioxane (10 mL) was added HCl in Dioxane (4.0 Msolution, 27.5 mL, 110.0 mmol) dropwise at n and was stirred for 4 h.The solvent was evaporated under vacuum to get crudehexahydro-1H-furo[3,4-c]pyrrol-1-one hydrochloride (2.5 g, 69%) whichwas directly used for the next step ¹H NMR (400 MHz, DMSO-D₂O): δ ppm4.46 (dd, >9.6, 7.5 Hz, 1H), 4.21 (dd, J=9.6, 2.7 Hz, 1H), 3.53-3.57 (m,1H), 3.41-0.3.49 (m, 5H), 3.31-3.37 (m, 1H), 3.19 (dd, J=12.0, 5.5 Hz,1H); m/z (ESI): 128.2 (M+H)⁺.

Step 4: To a mixture of hexahydro-1H-furo[3,4-c]pyrrol-1-onehydrochloride (2.0 g, 15.73 mmol) and 1,3-dichloro-5-iodobenzene (4.29g, 15.73 mmol) in toluene (20 mL) was added Cs₂CO₃ (10.25 g, 31.5 mmol),Xantphos (0.45 g, 0.787 mmol) followed bytris(dibenzylideneacetone)dipalladium(0) (0.360 g, 0.393 mmol) at rt andthen degassed with nitrogen for 2 mins. It was heated at 100° C. for 16h. The reaction mixture was filtered through celite pad and washed withEthyl acetate. The solvent was evaporated under vacuum to get crudewhich w as purified by flash column chromatography eluting with agradient of 30% to 40% EtOAc in petroleum ether to provide5-(3,5-dichlorophenyl)hexahydro-1H-furo[3,4-c]pyrrol-1-one (02.5 g, 9.19mmol, 58.4% yield) as light-yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δppm 6.79 (t, J=1.8 Hz, 1H), 6.64 (d, J=1.8 Hz, 2H), 4.48 (dd, J=9.3.6.0Hz, 1H), 4.25 (dd, J=9.2, 1.7 Hz, 1H), 3.56-3.76 (m, 1H), 3.4.3-3.55 (m,3H), 3.38 (d, J=14.5 Hz, 1H), 3.29-3.33 (m, 1H). m/z (ESI): 272.2, 274.2(M+H)⁺.

Step 5: To a solution of5-(3,5-dichlorophenyl)hexahydro-1H-furo[3,4-c]pyrrol-1-one (1.70 g, 6.25mmol) in methanol (20 mL) was added TMS-Br (8.11 mL, 62.5 mmol) at 0° C.dropwise and stirred for 5 min. Zinc bromide (0.422 g, 1.874 mmol) wasadded and the resultant reaction mixture was stirred for 48 h at rt. Thereaction was diluted with water and EtOAc. The organic extract wasseparated and washed with brine, dried over Na₂SO₄, filtered andconcentrated to provide yellow oil that was purified by columnchromatography eluting with a gradient of 10% to 15% EtOAc in petroleumether to provide methyl4-(bromomethyl)-1-(3,5-dichlorophenyl)pyrrolidine-3-carboxylate (1.20 g,3.27 mmol, 52.3% yield) as light-yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 6.71 (t, J=1.8 Hz, 1H), 6.53 (d, J=18 Hz, 2H), 3.51-3.63(m, 5H), 3.45 (td, J=6.8, 5.2 Hz, 1H), 3.34 (s, 3H), 3.24 (dd, J=9.7,7.0 Hz, 1H), 2.95-3.02 (m, 1H).

Step 6: To a solution of methyl4-(bromomethyl)-1-(3,5-dichlorophenyl)pyrrolidine-3-carboxylate (0.200g, 0.545 mmol) in tert-butanol (2 mL), was added potassium tert-butoxide(0.092 g, 0.817 mmol) at rt and was stirred for 1 h. The reactionmixture was filtered through celite pad and washed with Ethyl acetate(10 mL). The filtrate was washed with H₂O, brine, dried over Na₂SO₄,filtered and evaporated under vacuum. The crude product was purified byreverse-phase preparative HPLC (CH₃CN/H₂O, gradient 20% to 25% over 60min) to provide3-(3,5-dichlorophenyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid(0.080 g, 0.294 mmol, 54.0% yield) as off-white solid. ¹H NMR (400 MHz,DMSO-d₆): δ ppm 6.65 (t, J=1.8 Hz, 1H), 6.46 (d, J=1.8 Hz, 2H), 3.62 (d,J=9.7 Hz, 1H), 3.39-3.44 (m, 2H), 3.25 (dd, J=9.6, 4.5 Hz, 1H), 1.70(dt, J=8.5, 4.4 Hz, 1H), 1.30 (dd, J=7.9, 3.2 Hz, 1H), 0.37 (dd, J=4.6,3.3 Hz, 1H). m/z (ESI): 271.1 (M−H)⁺.

Intermediate W:N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-<3,5-dichlorophenyl)azepane-3-carboxamide

Step 1: To a solution of 1-(tert-butoxycarbonyl)azepane-3-carboxylicacid (0.5 g, 2.055 mmol) in CH₂Cl₂ was added Pyridine (0.499 mL, 6.17mmol), T₃P (0.981 g, 3.08 mmol) at 0° C. and stirred for 5 min. Then(1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-aminehydrochloride (0.428 g, 2.466 mmol) was added and stirred at roomtemperature for 16 h. The reaction was quenched with ice water,extracted with EtOAc, dried over Na₂SO₄, filtered and evaporated invacuo. This material was purified by silica gel chromatography using agradient of 80% ethyl acetate in petroleum ether to providetert-butyl-3-(((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)azepane-1-carboxylate(0.49 g, 1.352 mmol, 65.8% yield) as pale yellow viscous liquid. ¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.00-8.26 (m, 1H), 4.04-4.12 (m, 2H),3.52-3.72 (m, 2H), 2.95-3.15 (m, 2H), 2.40-2.61 (m, 2H), 2.07-2.23 (m,1H), 1.62-1.54 (m, 9H), 1.32-1.47 (m, 9H), 1.13-1.27 (m, 2H). m/z (ESI):361.3 (M−H)⁺.

Step 2: To a 25-mL round-bottomed flask was addedtert-butyl-3-(((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)azepane-1-carboxylate(0.3 g, 0.793 mmol) in 1,4-dioxane (4 mL) was treated with HCl (4 M inDioxane, 0.594 mL, 2.378 mmol) drop wise at ambient temperature andstirred for 4 h. The reaction mixture was concentrated under reducedpressure and the erode material was washed with hexane twice to getN-((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.]heptan-2-yl)azepane-3-carboxamide(0.2 g, 0.633 mmol, 80% yield) as a tan solid.

Step 4: To a solution ofN-((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)azepane-3-carboxamide(0.116 g, 0.366 mmol) in tetrahydrofuran (4 mL) was added LiHMDS (0.184g, 1.099 mmol) under nitrogen atmosphere at 0° C. and was stirred at RTfor 5 min. Another flask was charged with 1,3-dichloro-5-iodobenzene(0.1 g, 0.366 mmol) in tetrahydrofuran (4 mL) followed by Ruphosprecatalyst (5.34 mg, 7.33 μmol), Ruphos (3.42 mg, 7.33 μmol) and wasdegassed with N₂ gas for 5 min. This resultant reaction mixture wasadded to the first one and was stirred at 60° C. for 16 h. The reactionmixture was filtered through celite, and washed with H₂O and EtOAc. Theorganic layer was separated, washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The crude material was purified byPrep-HPLC to provide1-(3,5-dichlorophenyl)-N-((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)azepane-3-carboxamide(0.02 g, 0.049 mmol, 13.40% yield) as an off white solid. ¹H NMR (400MHz, DMSO-d₆): δ ppm 8.24 (t, J=5.3 Hz, 1H), 6.54-6.87 (m, 3H), 4.10(dt, J=19.7, 5.1 Hz, 3H), 3.61-3.84 (m, 2H), 3.38-3.44 (m, 2H), 3.24(dd, J=14.2, 8.7 Hz, 1H), 2.71-2.81 (m, 1H), 2.18 (q, J=13.1, 10.5 Hz,1H), 1.73-1.98 (m, 4H), 1.45-1.72 (m, 4H), 1.20-1.38 (m, 2H). m/z (ESI):407.2 (M+H)⁺.

Intermediate X: 3-<2,5-Dichlorophenyl)cyclopentane-1-carboxylic acid

The mixture of methyl cyclopent-3-ene-1-carboxylate (0.25 mL, 2.0 mmol),1,4-dichloro-2-iodobenzene (0.27 mL, 2.0 mmol), palladium acetate (0.2mmol), DIEA (0.36 mL, 2.0 mmol), water (1 mL) and acetonitrile (5.0 mL)was degassed and flushed with nitrogen. After stirring at 85° C. for 3h, the resulting mixture was cooled and diluted with EtOAc and brine.The organic layer was dried over Na₂SO₄, concentrated under reducedpressure and purified by silica gel column chromatography (15-20%EtOAc/Hex) to afford methyl3-(2,5-dichlorophenyl)cyclopent-3-ene-1-carboxylate (432 mg, 80%) as anoil.

Methyl 3-(2,5-dichlorophenyl)cyclopent-3-ene-1-carboxylate (44 mg, 0.16mmol), PtO₂ (10 mg, 0.044 mmol), and methanol (2.0 mL) were stirred atroom temperature for 2 h under 1 atm hydrogen pressure (balloon). Theresulting mixture was filtered through celite and concentrated underreduced pressure to provide crude methyl3-(2,5-dichlorophenyl)cyclopentane-1-carboxylate.

Methyl 3-(2,5-dichlorophenyl)cyclopentane-1-carboxylate (crude from theprevious reaction, 0.16 mmol), NaOH (aq IN, 1.0 mL, 1.0 mmol), THF (1.0mL) and methanol (1.0 mL) were stirred at room temperature for 1 h. Theresulting mixture was diluted with water and washed with EtOAc twice.The resulting aqueous layer was acidified with 1N aq. HCl and extractedwith EtOAc. The organic layer was dried over Na₂SO₄, concentrated underreduced pressure to afford the desired product (31 mg, 75%) which wasused in the next step without further purification. MS (EI) forC₁₂H₁₂Cl₂O₂, found 257.0 [M−1].

Intermediate Y:2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

To a reaction vial was added, potassium acetate (0.747 g, 7.61 mmol),PdCl₂(dppf)-DCM adduct (0.207 g, 0.254 mmol), bis(pinacolato)diboron(0.967 g, 3.81 mmol),4-bromo-2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)benzamide(0.900 g, 2.54 mmol), and 1,4-dioxane (12.69 ml). The vial was purgedwith nitrogen and sealed. The vial was heated to 80° C. for 3 hours. Thereaction mixture was poured directly onto an ISCO loading cartridge andpurified by chromatography, eluting with a gradient of 0% to 50% EtOAcin Heptane to provide2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(0.659 g, 0.412 mmol, 81.0% yield) as off-white solid, m/z 320.0 [M+1]

The intermediates below were made by identical procedures

Int. Structure Name LC/MS data Y-1

N-(1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide m/z: 382.0 [M +1] Y-2

N-(1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide m/z: 386.0 [M +1] Y-3

N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-2-(trifluoromethyl)benzamide m/z:436.0 [M + 1]

Intermediate Z:N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-isobutoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Intermediate Z was prepared in an identical way to Intermediate Mfollowed borylation as described for intermediate Y.N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-isobutoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(1.02 g, 2.32 mmol, 70.1% yield) was obtained as an off-white solid,m/z: 440.0 [M+1]

Intermediate AA:2-chloro-3-isobutoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid

Step 1: To a stirred solution of methyl 3-hydroxybenzoate (2.00 g, 13.15mmol) in ethanol (6.57 ml) was added iodine (1.335 g, 5.26 mmol) in oneportion. The reaction was healed to reflux before an aqueous solution (2mL) of iodic acid (0.462 g, 2.63 mmol) was added. The mixture wasrefluxed for 1 hour before it was cooled to room temperature. Theproduct was recovered by filtration and washed with water to give methyl3-hydroxy-4-iodobenzoate (2.78 g, 10.00 mmol, 76% yield) as a whitesolid (m/z: 279.0 [M+1]) and was used for the next step directly.

Step 2: A mixture of methyl 3-hydroxy-4-iodobenzoate (1.39 g, 5.00 mmol)and 2,2,6,6-tetramethylpiperidine (7.06 mg, 0.050 mmol) in toluene (50.0ml) was heated to 100° C. Then, sulfuryl chloride (0.675 g, 5.00 mmol)dissolved in toluene (50 ml) was added dropwise. The mixture was stirredat 100° C. for 1 hour. Upon completion, the reaction was cooled to roomtemperature and the product was recovered by filtration and washed withtoluene to give methyl 2-chloro-3-hydroxy-4-iodobenzoate (1.30 g, 4.16mmol, 83% yield) as a white solid m/z: 313.2 [M+1]

Step 3: Performed as in Intermediate M. Step 1. methyl2-chloro-4-iodo-3-isobutoxybenzoate (0.423 g, 1.148 mmol, 71.7% yield),m/z: 369.2 [M+1]

Step 4: Performed as in Method 19 to provide methyl2-chloro-3-isobutoxy-4-(4-methyl-1H-pyrazol-1-yl)benzoate (0.046 g,0.143 mmol, 52.5% yield), m/z: 323.2 [M+1]

Step 5: Performed as in Intermediate M step 2.2-chloro-3-isobutoxy-4-(4-methyl-1H-pyrazol-1-yl)benzoic acid (0.042 g,0.136 mmol, 50% yield), m/z: 309.0 [M+1]

The intermediates below w ere made by identical procedures

Int. Structure Name LC/MS data AA- 1

3-isobutoxy-4-(4-methyl-1H-pyrazol-1- yl)benzoic acid m/z: 275.0 [M + 1]

Intermediate AB:2-chloro-3-isobutoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid

Methyl 2-chloro-3-hydroxy-4-iodobenzoate was converted to2-chloro-3-isobutoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid (0.055 g,0.178 mmol, 65.7% yield) using the procedure for Intermediate Q. m/z:309.0 [M+1]

Synthetic Examples

The following examples are labeled using a classification system inwhich the first number refers to the method used to synthesize thecompound, the second number is an identifying number, and the thirdnumber, if present, refers to the compound's order of elution in achromatographic separation process where stereochemistry if shown isarbitrarily defined. If the third number is absent, the compound is asingle compound or mixture of isomers. The sequential numbering of theExamples is interrupted and certain Example numbers are intentionallyomitted due to formatting considerations.

Method 1:

Example 1-1:N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(1H-pyrrol-1-yl)benzo[d]thiazole-6-carboxamide

A 4 ml vial containing 2-<1H-pyrrol-1-yl)benzo[d]thiazole-6-carboxylicacid (0.2 mmol) was treated with a solution of Intermediate A in DMF(0.25 mmol). A solution of T3P in DMF (0.255 ml, 0.400 mmol) was added.Followed by a solution of pyridine and triethylamine. The vial wassealed and agitated on a shaker plate for 18 hrs. The reaction wasquenched with 1 ml of a 10% 1M NaOH solution in wet DMF and purified byRP-HPLC (Purification performed with 0.1% NH4OH in H2O (A) and ACN (B)as mobile phase, XSelect column (19×100 mm, 10 um). MS mode: ESI+).Fractions containing the product were concentrated to provide the titlecompound: LC/MS

Method 2:

Example 2-1-1 and 2-1-2:2-(4-chloro-3-(trifluoromethyl)phenoxy)-N-(-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamideendo enantiomer 1 and2-(4-chloro-3-(trifluoromethyl)phenoxy)-N-((1S,2S,4R)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamideendo Enantiomer 2

To red cap vials were added2-(4-chloro-3-(trifluoromethyl)phenoxy)acetic acid (0.12 g, 0.471 mmol)and HATU (0.358 g, 0.943 mmol) in DMF (2.5 ml) followed by Hunig's base(0.41 ml, 2.357 mmol). They were stirred at n for 5 min and racemicIntermediate A (0.131 g, 0.754 mmol) was added. They were stirred at rtfor 10 min. LCMS showed conversion to desired product. The erodematerial was absorbed onto a plug of silica gel and purified bychromatography through a 10 g×2 biotage ultra column, eluting with agradient of 10% to 50% EtOAc:EtOH (3:1) in Heptane, to provide racemic2-(4-chloro-3-(trifluoromethyl)phenoxy)-N-((1S,2S,4R)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide(0.05 g, 0.134 mmol, 28.4% yield) product as yellow solid, m/z: 374.0[M+1] ¹H NMR (500 MHz, DMSO-d₆) δ 8.42 (br d, J=5.58 Hz, 1H), 7.65 (d,J=8.82 Hz, 1H), 7.38 (d, J=2.98 Hz, 1H), 7.28 (dd, J=3.05, 8.89 Hz, 1H),4.64-4.71 (m, 2H), 4.10-4.16 (m, 3H), 2.13-2.20 (m, 1H), 1.74-1.83 (m,2H), 1.55-1.67 (m, 2H), 1.36 (dd, J=4.15, 12.85 Hz, 1H) The sample waspurified by SFC using an Whelk-01-S,S, 21×250 mm, 5 micron column, amobile phase of 30% isopropanol using a flow rate of 110 mL/min togenerate 11 mg of 2-1-1 with ee>99% and 8 mg of 2-1-2 with ee>96%.

Method 3:

Example 3-1-1 and 3-1-2:3-(3-chlorophenyl)-N-((1S,2S,4R)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)isoxazole-5-carboxamideand3-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)isoxazole-5-carboxamide

Step 1: To a mixture of 3-(3-chlorophenyl)-1,2-oxazole-5-carboxylic acid(0.619 ml, 2.77 mmol), and racemic-endo-tert-butyl(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate (0.263 g,1.597 mmol) in dichloromethane (5.89 ml) was added triethylamine,anhydrous (0.809 ml, 5.76 mmol) and T3P in DMF (2.427 ml, 4.16 mmol).The reaction mixture was stirred at 20° C. for 12 h. LC/MS showedcompletion conversion to the amide. Saturated NaHCO₃ solution was addedand the mixture was stirred for 5 min. The mixture was partitioned in aphase separator. The organic layer was collected and concentrated. Thecrude material was absorbed onto a plug of silica gel and purified bychromatography through a 40 g Redi-Sep GOLD pre-packed silica gelcolumn, eluting with a gradient of 0% to 60% EtOAc in heptane, toprovide rac-tert-butyl(1R,2R,4S)-2-(3-(3-chlorophenyl)isoxazole-5-carboxamido)-7-azabicyclo[2.2.1]heptane-7-carboxylate(0.401 g, 0.960 mmol 81% yield) as a white solid.

Step 2: To a solution of rac-tert-butyl(1R,2R,4S)-2-(3-(3-chlorophenyl)isoxazole-5-carboxamido)-7-azabicyclo[2.2.1]heptane-7-carboxylate(0.071 g, 0.170 mmol) in dichloromethane (0.850 ml) was added2,2,2-trifluoroacetic acid (0.484 ml, 4.25 mmol). The mixture wasstirred at it for 12 h. LC/MS showed complete Boc deprotection. Themixture was passed through a 5 g SCX-2 Column with the aid of MeOH. Thebasic components were eluted with 2M NH₃ in MeOH and concentrated toproviderac-N-((1R,2R,4S)-7-azabicyclo[2.2.1]heptan-2-yl)-3-(3-chlorophenyl)isoxazole-5-carboxamide

Step 3: The solid obtained in step 2 was dissolved in tetrahydrofuran(0.850 ml). Potassium carbonate (0.070 g, 0.510 mmol) was added followedby cyanic bromide, 5 M solution in acetonitrile (0.037 ml, 0.187 mmol).The mixture was stirred at rt for 12 h. LC/MS showed completion of thereaction. The mixture was partitioned between water and DCM. The organiclayer was collected and concentrated. The crude material was absorbedonto a plug of silica gel and purified by chromatography through aBiotage Ultra 10 g pre-packed silica gel column, eluting with a gradientof 0% to 50% EtOAc in heptane, to provide a white solid, chiralpurification was performed via preparative SFC, to give 3-1-1 (>99%ee, >99% chemical purity) and 3-1-2 (95.22% ee, 96.49% chemical purity)which were arbitrarily assigned stereochemistry, m/z: 343.16 [M+1] ¹HNMR (500 MHz, DMSO-d₆) δ 9.30 (d, J=6.23 Hz, 1H), 8.01 (t, J=1.69 Hz,1H), 7.92 (d, J=7.41 Hz, 1H), 7.77 (s, 1H), 7.56-7.64 (m, 2H), 4.22-4.33(m, 2H), 4.18 (t, J=4.80 Hz, 1H), 3.32 (s, 15H), 2.17-2.25 (m, 1H),1.85-1.92 (m, 1H), 1.77-1.85 (m, 1H), 1.64-1.74 (m, 2H), 1.62 (dd,J=4.67, 12.85 Hz, 1H)

Method 4:

Example 4-1-1, 4-1-2, 4-1-3, and 4-1-4:(1S,2S,4R)-7-cyano-N-(4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-7-azabicyclo[2.2.1]heptane-2-carboxamide;(1S,2R,4R)-7-cyano-N-(4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-7-azabicyclo[2.2.1]heptane-2-carboxamide;(1R,2S,4S)-7-cyano-N-(4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-7-azabicyclo[2.2.1]heptane-2-carboxamide;and(1R,2R,4S)-7-cyano-N-(4-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-7-azabicyclo[2.2.1]heptane-2-carboxamide

7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane-2-carboxylic acid(0.5 g 1.05 equiv.) and 4-(3-(trifluoromethyl)phenyl)thiazol-2-amine(1.0 equiv.) were weighed to an 8 ml vial. I-propanephosphonic acidcyclic anhydride, 50 wt. % solution in ethyl acetate (2.51 ml, 3.95mmol) was added followed by pyridine and the reaction was stirred atr.t. for 3 hr when full consumption of the acid was observed. SaturatedNaHCO₃ was added and the reaction was extracted with EtOAc 3×. Thecombined organics were washed with 1N HCl, brine, dried over Na₂SO₄,filtered and concentrated. The orange foam obtained was brought up in˜0.5 ml of DCM and treated with ˜1 ml of TFA and allowed to stand o/n.After concentrating the crude oil was azeotroped 1× with heptane, wasbrought up in tetrahydrofuran (9.87 ml) and treated with K₂CO₃ (1.1 g 4equiv.) for a few minutes before cyanic bromide (5M acetonitrile, 0.434ml, 2.171 mmol) was added. After 1 hour the reaction was quenched withwater, extracted 3× with EtOAc. and the combined organics were washedwith sat NaHCO₃. The organics were separated, concentrated and purifiedby SFC: Chiralpak IC 3×15 cm, 5 micron column, a mobile phase of 20%methanol using a flowrate of 80 mL/min. to generate 137 mg of 4-1-1 withan ee of >99%, 135 mg of 4-1-2 with an ee of >98%, m/z=393.0 (M+H), ¹HNMR (500 MHz, DMSO-d₆) δ 8.23 (s, 1H), 8.19 (br t, J=3.57 Hz, 1H), 7.86(s, 1H), 7.63-7.69 (m, 2H), 4.47 (t, J=4.74 Hz, 1H), 4.22 (t, J=4.28 Hz,1H), 3.30-3.49 (m, 1H), 1.93-2.05 (m, 2H), 1.76-1.85 (m, 1H), 1.64-1.76(m, 1H), 1.46-1.57 (m, 2H) 118 mg of 4-1-3 with an ee of >96% and 124 mgof 4-1-4 with an ee of >98%. m/z=393.0 (M+H) ¹H NMR (500 MHz, DMSO-d₆) δ8.24 (s, 1H), 8.17-8.22 (m, 1H), 7.83 (s, 1H), 7.66 (d, J=4.89 Hz, 2H),4.44 (d, J=4.54 Hz, 1H), 4.22 (t, J=4.48 Hz, 1H), 2.89 (dd, J=5.13, 9.02Hz, 1H), 2.15-2.26 (m, 1H), 1.72-1.90 (m, 3H), 1.62-1.71 (m, 1H),1.51-1.62 (m, 1H). Peak assignment determined by SFC: Chiralpak IC, 15%methanol.

Method 5;

Example 5-1:N-((1S,2S,4R)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4,6-dimethylpyrimidin-2-yl)indoline-5-carboxamide

A glass microwave reaction vessel was charged with2-chloro-4,6-dimethyl-1,3-diazine (0.023 g, 0.163 mmol),N-((1S,2S,4R)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)indoline-5-carboxamidehydrochloride (0.04 g, 0.125 mmol), Ruphos pd G1 methyl t-butyl etheradduct (0.020 g, 0.025 mmol) and cesium carbonate (0.143 g, 0.439 mmol).The reaction vial was purged with N₂ and tBuOH (0.6 ml) was added. Thereaction mixture was heated in a microwave reactor at 120° C. for 10min. LCMS showed desired product formation. The reaction mixture werediluted with water and extracted with DCM. The organic extracts wereconcentrated. The crude material was absorbed onto a plug of silica geland purified by chromatography through a 10 g Biotage ultra column,eluting with a gradient of 10% to 60% EtOAc/EtOH (3/1) in heptane, toN-((1S,2S,4R)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4,6-dimethylpyrimidin-2-yl)indoline-5-carboxamideas off-white solid. m/z: 389.0 [M+1] ¹H NMR (500 MHz, DMSO-d₆) δ 8.42(d, J=9.08 Hz, 1H), 8.36 (d, J=6.10 Hz, 1H), 7.74 (s, 1H), 7.75 (d,J=6.32 Hz, 1H), 6.74 (s, 1H), 4.26-4.32 (m, 1H), 4.20-4.25 (m, 3H),4.1.3-4.19 (m, 1H), 3.18 (t, J=8.69 Hz, 2H), 2.36-2.43 (m, 6H), 2.19 (brs, 1H), 1.77-1.89 (m, 2H), 1.62-1.72 (m, 2H), 1.56 (dd, J=4.80, 12.85Hz, 1H)

Method 6:

Example 6-1:N-(racemic-(endo)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methylpyrimidin-2-yl)-1H-indole-5-carboxamide

A glass microwave reaction vessel was charged withN-((1S,2S,4R)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1H-indole-5-carboxamide(0.04 g, 0.143 mmol), 2-chloro-4-methylpyrimidine (0.024 g, 0.183 mmol),cesium carbonate (0.093 g, 0.285 mmol), palladium (ii) acetate (9.61 mg,0.043 mmol), and racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(0.027 g, 0.043 mmol) in a mixture of 1,4-dioxane (0.7 ml) andtert-butanol (0.7 ml). The reaction mixture was purged with N₂, stirredand heated in an Initiator microwave reactor at 120° C. for 6 min. LCMSshowed nearly full conversion to desired product. Then the orangereaction mixture was diluted with water and extracted with DCM. Theorganic extract was concentrated in vacuo to give the crude material asan orange solid. The crude material was absorbed onto a plug of silicagel and purified by chromatography through a 10 g biotage ultra column,eluting with a gradient of 10% to 60% EtOAc/EtOH in Heptane, to providea racemic mixture ofN-((1S,2S,4R)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methylpyrimidin-2-yl)-1H-indole-5-carboxamide(0.013 g, 0.035 mmol, 24% yield) as a light-yellow solid, m/z: 373.2[M+1] ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (d, J=8.81 Hz, 1H), 8.74 (d,J=5.08 Hz, 1H), 8.57 (d, J=5.91 Hz, 1H), 8.36 (d, J=3.63 Hz, 1H), 8.21(d, J=1.66 Hz, 1H), 7.84 (dd, J=1.76, 8.81 Hz, 1H), 7.28 (d, J=4.98 Hz,1H), 6.90 (d, J=3.63 Hz, 1H), 4.34 (br dd, J=4.72, 11.14 Hz, 1H), 4.26(t, J=4.51 Hz, 1H), 4.17 (t, J=4.72 Hz, 1H), 2.59 (s, 3H), 2.23 (br s,1H), 1.87-1.96 (in, 1H), 1.78-1.86 (m, 1H), 1.66-1.75 (m, 2H), 1.60 (dd,J=4.72, 12.80 Hz, 1H)

Method 7:

Example 7-1:N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyclopropylpyrimidin-2-yl)-N-methylindoline-5-carboxamide

To a glass reaction vial were added Intermediate A, peak 1 derivedN-((1S,2S,4R)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyclopropylpyrimidin-2-yl)indoline-5-carboxamide(0.03 g, 0.075 mmol) in tetrahydrofuran (0.5 ml) followed by NaH (60% inmineral oil) (5.4 mg, 0.135 mmol). It w as stirred at it for 5 min, thenMel (0.012 ml, 0.187 mmol) was added. The reaction mixture was stirredat rt for 0.5 h. LCMS showed full conversion to desired product. Thereaction mixture was diluted with water and extracted with DCM. Theorganic extract was washed with saturated NaCl and dried over MgSO₄. Thesolution was filtered and concentrated in vacuo to give the etudematerial as a light-yellow solid, m/z: 415.3 [M+1] ¹H NMR (400 MHz,DMSO-d₆) δ 8.37 (d, J=5.08 Hz, 1H), 8.24 (d, J=8.19 Hz, 1H), 7.34 (s,1H), 7.33 (d, >9.57 Hz, 1H), 6.89 (d, >5.08 Hz, 1H), 4.46 (t, J=4.30 Hz,1H), 4.14-4.23 (m, 4H), 3.17 (t, J=8.81 Hz, 2H), 2.96 (s, 3H), 2.04-2.22(m, 2H), 1.81-1.90 (m, 2H), 1.66-1.75 (m, 2H), 1.05-1.14 (m, 4H)

Method 8:

Example 8-1:N5-((1S,2S,4R)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N1-cyclopropylindoline-1,5-dicarboxamide

To a glass vial was added Intermediate A, peak 1 derivedN-((1S,2S,4R)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)indoline-5-carboxamidehydrochloride (0.05 g, 0.157 mmol) and cyclopropyl isocyanate (0.013 g,0.157 mmol) in dichloromethane (0.627 ml) followed by Et₃N (0.057 ml,0.408 mmol). It was stirred at rt for 6 h. and LCMS showed nearly fullconversion to desired product. The reaction was quenched with water andextracted with DCM. The organics were concentrated and the purificationwas done using HPLC with 0.1% NH4OH in ACN and water as mobile phasem/z: 366.2 [M+1] ¹H NMR (600 MHz, DMSO-d₆) δ 8.32 (d, J=6.07 Hz, 1H),7.86 (d, J=8.33 Hz, 1H), 7.66 (s, 1H), 7.65 (d, >7.10 Hz, 1H), 6.84(d, >2.65 Hz, 1H), 4.23-4.29 (m, 1H), 4.20 (t, J=4.48 Hz, 1H), 4.14 (t,J=4.79 Hz, 1H), 3.87 (t, J=8.80 Hz, 2H), 3.12 (t, J=8.76 Hz, 2H), 2.59(tdd, J=3.56, 6.99, 10.41 Hz, 1H), 2.14-2.20 (m, 1H), 1.76-1.87 (m, 2H),1.61-1.71 (m, 2H), 1.55 (dd, J=4.67, 12.69 Hz, 1H), 0.58-0.64 (m, 2H),0.47-0.53 (m, 2H)

Method 9:

Example 9-1:N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzamide

A glass microwave reaction vessel was charged with Intermediate A peak 1derived4-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-methylbenzamide(0.083 g, 0.247 mmol), 1-methylpyrazole-4-boronic acid pinacol ester(0.077 g, 0.371 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]pd(II)methyl-tert-butylether (0.0.37 g, 0.049 mmol) in K₃PO₄ (1M, aq.) (0.50ml, 0.50 mmol) and dioxane (1.3 ml). The reaction mixture was stirredand heated in a microwave reactor at 120° C. for 12 min. LC/MS showedfull conversion to desired product. The reaction mixture was dilutedwith water and extracted with DCM. The organic extract was washed withsaturated NaCl and concentrated to give the crude material as an orangeoil. The crude material was absorbed onto a plug of silica gel andpurified by chromatography through a 10 g biotage ultra column, elutingwith a gradient of 10% to 70% EtOAc/EtOH (3/1) in Heptane, to provideN-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzamide(0.067 g, 0.200 mmol, 81% yield) as an off white solid, m/z: 366.2 [M+1]¹H NMR (500 MHz, DMSO-d₆) δ 8.49 (d, J=5.97 Hz, 1H), 8.04 (s, 1H), 7.76(s, 1H), 7.74 (s, 1H), 7.69 (dd, J=1.62, 7.98 Hz, 1H), 7.49 (d, J=8.04Hz, 1H), 4.22-4.33 (m, 2H), 4.16 (t, J=4.74 Hz, 1H), 3.90 (s, 3H), 2.44(s, 3H), 2.17-2.24 (m, 1H), 1.77-1.90 (m, 2H), 1.63-1.73 (m, 2H), 1.57(dd, J=4.67, 12.72 Hz, 1H)

Method 10:

Example 10-1:2-((3-Bromobenzyl)(methyl)amino)-N-(racemic-(endo)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide

The mixture of2-bromo-N-(racemic-(endo)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide3 (4.0 mg, 0.015 mmol), 1-(3-bromophenyl)-N-methylmethanamine (3.1 mg,0.015 mmol), DIEA (5.0 μL, 0.0.3 mmol) and DMSO (0.3 mL) was stirred atroom temperature for 2 h. The resulting mixture was purified bypreparative HPLC (NH₄OAc) to afford the product (racemic, AcOH salt 6.3mg, 82%) as a white solid after lyophilization. MS (EI) for C₁₇H₂₁BrN₄O,found 377.0 (M+1).

Method 11:

Example 11-1:2-(4-Chloro-2-cyclohexylphenoxy)-N-(racemic-(endo)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide

The mixture of2-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide(racemate, 5.0 mg, 0.019 mmol), 4-chloro-2-cyclohexylphenol (4.0 mg,0.019 mmol), potassium carbonate (3.9 mg, 0.029 mmol) and DMF (0.4 mL)was stirred at room temperature for 1 h. The resulting mixture waspurified by preparative HPLC (0.1% AcOH) to afford the product (racemic,4.7 mg, 82%) as a white solid after lyophilization. MS (EI) forC₂₁H₂₆ClN₃O₂, found 388.0 (M+1).

Method 12:

Example 12-1:racemic-(endo)-2-(4-((4-Chlorophenyl)thio)piperidine-1-carbonyl)-7-azabicyclo[2.2.1]heptane-7-carbonitrile(Racemic)

To a stirred solution of cruderacemic-(endo)-7-cyano-7-azabicyclo[2.2.1]heptane-2-carboxylic acid(Intermediate I) 4-((4-chlorophenyl)thio)piperidine (11 mg, 0.050 mmol),HATU (29 mg, 0.075 mmol) and DMF (0.5 mL) was added DIEA (0.026 mL, 0.15mmol) at room temperature. After stirring for 20 min, the mixture waspurified by preparative HPLC (0.1% AcOH) to affordracemic-(endo)-2-(4-((4-chlorophenyl)thio)piperidine-1-carbonyl)-7-azabicyclo[2.2.1]heptane-7-carbonitrile(5.0 mg, 27%, 2 steps) as a white solid after lyophilization MS (EI) forC₁₉H₂₂ClN₃OS, found 453.1 (M+1).

Method 13:

Example 13-1:N-(racemic-(endo)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methylpyrimidin-2-yl)indoline-5-carboxamide

Step 1: To a glass reaction vial containing1-(4-methylpyrimidin-2-yl)indoline-5-carboxylic acid (0.087 g, 0.340mmol) was added oxalyl chloride (0.049 ml, 0.557 mmol) indichloromethane (0.619 ml) followed by 2 drops of DMF at rt. Thereaction was stirred at rt for 0.5 h. when LC/MS showed startingmaterial was consumed. The reaction was concentrated and used in thenext step directly.

Step 2: To a glass reaction vial containing crude product from step 1was added racemic Intermediate A (0.064 g, 0.371 mmol) and triethylamine(0.216 ml, 1.547 mmol) in dichloromethane (0.619 ml). The reactionmixture were stirred at rt for 15 min. LC/MS showed desired productformation. The reaction mixture was quenched with water and extractedwith DCM. The crude material was absorbed onto a plug of silica gel andpurified by chromatography through a 10 g biotage ultra column, elutingwith a gradient of 10% to 55% EtOAc/EtOH (3/1) in Heptane, to provideN-(racemic-(endo)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methylpyrimidin-2-yl)indoline-5-carboxamide(38.7 mg, 0.103 mmol, 33% yield) as a white solid.

Method 14;

Example 14-1:N-(racemic-(endo)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(pyrimidin-2-ylamino)benzamide(Racemic)

Step 1: To a glass reaction vial were added4-(pyrimidin-2-ylamino)benzoic acid (100 mg, 0.465 mmol) and thionylchloride (237 μl, 3.25 mmol) in dichloromethane (1.2 ml) followed by 2drops of DMF under rt. It was stirred at rt for 0.5 h. LCMS proveddesired product formation by quenched LCMS sample with MeOH. It wasconcentrated and dried on high vacuum to yield4-(pyrimidin-2-ylamino)benzoyl chloride (0.12 g, 0.514 mmol, 111% yield)as off white solid.

Step 2: Performed as in Method 13, step 2 to provide 29 mg of racemicN-(racemic-(endo)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(pyrimidin-2-ylamino)benzamidem/z: 335.2 [M+1].

Method 15:

Example 15-1:6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methylpyrimidin-2-yl)indoline-5-carboxamide

To a red cap vial was added6-chloro-N-((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methylpyrimidin-2-yl)indoline-5-carboxamide(0.04 g, 0.079 mmol) and K₂CO₃ (0.025 g, 0.183 mmol) in 1,4-dioxane(0.36 ml) followed by cyanogen bromide solution, 5.0 m in acetonitrile(0.032 ml, 0.159 mmol). The heterogeneous mixture was stirred at rt for1 h. LC/MS showed full conversion to the desired product. The reactionmixture was quenched with sat. NaHCO₃ aq. and extracted with DCM Theorganic extract was concentrated and purified under reverse phase columnwith 0.1% NH4OH in ACN and water as mobile phase to yield 20 mg ofdesired product, m/z: 409.0 [M+1]. ¹H NMR (600 MHz, DMSO-d₆) δ 8.64(brd, J=5.60 Hz, 1H), 8.50 (d, J=4.98 Hz, 1H), 8.41 (s, 1H), 7.31 (s,1H), 6.88 (d, J=4.98 Hz, 1H), 4.21-4.26 (m, 4H), 4.09-4.19 (m, 1H), 3.20(br s, 1H), 3.16 (t, J=8.68 Hz, 2H), 2.44 (s, 3H), 2.15-2.24 (m, 1H),1.99 (ddd, J=4.17, 8.99, 12.85 Hz, 1H), 1.75-1.86 (m, 1H), 1.66-1.74 (m,1H), 1.56-1.65 (m, 1H), 1.40 (dd, J=4.01, 12.81 Hz, 1H)

Method 16:

Example 16-1:5-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)thiazole-2-carboxamide

Step 1

Performed as in Method1,5-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)thiazole-2-carboxamidewas obtained in 74% yield.

Step 2

To a 8 mL vial was added5-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)thiazole-2-carboxamide(21 mg, 0.064 mmol), 3-chlorophenylboronic acid (15.05 mg, 0.096 mmol),(1,1′-bis(diphenylphosphino) ferrocene) dichloropalladium (4.70 mg, 6.42μmol) and cesium carbonate (62.7 mg, 0.193 mmol), 1,4-dioxane (160 μl)and water (53.5 μl) was then added and the solution was sparged with Arfor 1 min before sealed and heated to 80° C. LC-MS at 1 h showedcompletion of the reaction to the desired product Water (1 mL) was addedand the aqueous layer was extracted with DCM (5 mL×3). The organicextracts were combined and concentrated under vacuum. The yellow residuewas applied to silica column chromatography (4 g Biotage column, elutingwith a gradient of 0%-80% EA in Heptane) to afford5-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)thiazole-2-carboxamide(16.0 mg, 0.045 mmol, 70% yield) as an off-white solid, m/z: 359.0 [M+1]¹H NMR (500 MHz, CHLOROFORM-d) δ 8.00-8.02 (m, 1H), 7.61 (td, J=1.17,1.82 Hz, 1H), 7.45-7.53 (m, 1H), 7.38-7.43 (m, 2H), 7.23-7.28 (m, 1H),4.51-4.57 (m, 1H), 4.41-4.45 (m, 1H), 4.14 (t, >5.13 Hz, 1H), 2.57(dddd, J=2.98, 5.16, 11.13, 13.04 Hz, 1H), 2.07-2.16 (m, 1H), 1.94-2.02(m, 2H), 1.66-1.72 (m, 1H), 1.24-1.31 (m, 1H).

Method 17;

Example 17-1:7-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxamide

Triphosgene (0.145 g, 0.490 mmol, aldrich) was dissolved in DCM andtreated with 3 drops of DMF.7-chloro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (0.15 g, 0.817 mmol,enamine) was added and the reaction was stirred at r.t. for 2 hoursbefore being concentrated. The crude chloro-formamide was dissolved inDCM and Intermediate A (0.142 g, 0.817 mmol) was added followed bytriethylamine. After 1 hour complete conversion was observed and thereaction was diluted with water and extracted with EtOAc 3×. Thecombined organics were combined, dried over Na2SO4, filtered,concentrated and purified via mass-directed reverse phase purificationto provide 17-1 as a white solid (0.103 g, 36% yield), m/z: 347.0 [M+1]¹H NMR (DMSO-d6) δ: 7.41 (d, J=2.4 Hz, 1H), 7.22 (dd, J=8.5, 2.6 Hz,1H), 6.98 (d, J=8.6 Hz, 1H), 6.56 (brd, J=5.1 Hz, 1H), 4.54 (d, J=15.7Hz, 1H), 4.46 (d, J=15.7 Hz, 1H), 4.03-4.11 (m, 2H), 3.89-4.03 (m, 3H),3.76-3.84 (m, 1H), 3.61-3.69 (m, 1H), 2.04-2.12 (m, 1H), 1.69-1.78 (m,1H), 1.52-1.61 (m, 2H), 1.45-1.52 (m, 1H), 1.36 (dd, J=12.6, 4.7 Hz, 1H)Method 18;

Example 18-1:7-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxamide

Intermediate A (0.2 g, 1.152 mmol) was dissolved in DCM and treated withphenyl chloroformate (0.180 g, 0.144 ml, 1.152 mmol) at rt for 2 hoursbefore being quenched with water. The reaction was diluted with EtOAc,the organics were separated and the aq. layer was re-extracted 2× withEtOAc. The combined organics were washed with brine, dried over Na2SO4,filtered and concentrated. The crude was dissolved in acetonitrile and7-chloro-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (0.210 g, 1.152mmol, combi-blocks) was added followed by pyridine and the reaction wasallowed to stir for 12 hrs when a mixture of phenol-carbamate of bothamines was observed along with benzodiazepine starting material andproduct. The reaction was heated to 65° C. for 4 hours, concentrated andpurified via mass-directed, reverse phase purification to provide 18-1in low yield (0.004 g, 1% yield), m/z: 3460 [M+1] ¹H NMR (DMSO-d6) δ:7.25 (br s, 1H), 7.03 (dd, J=8.5, 1.7 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H),6.40 (br d, J=5.2 Hz, 1H), 5.71 (br s, 1H), 4.41 (d, J=15.6 Hz, 1H),4.32 (d, J=15.6 Hz, 1H), 4.03-4.08 (m, 1H), 4.01 (t, J=4.5 Hz, 1H), 3.94(br dd, J=10.5, 4.8 Hz, 1H), 3.61 (td, J=6.7, 4.2 Hz, 1H), 3.39-3.48 (m,1H), 3.04-3.11 (m, 1H), 2.97-3.04 (m, 1H), 2.05-2.12 (m, 1H), 1.70-1.77(m, 1H), 1.59-1.66 (m, 1H), 1.52-1.58 (m, 1H), 1.46-1.52 (m, 1H), 1.37(dd, J=12.6.4.6 Hz, 1H)

Method 19:

Example 19-1:1-(6-acetamidopyridin-2-yl)-6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1H-indazole-5-carboxamide

A glass microwave reaction vessel was charged with2-(acetylamino)-3-bromopyridine (0.082 g, 0.380 mmol, Combi-BlocksInc.). Intermediate C-2 (0.06 g, 0.190 mmol), copper(i) iodide (14 mg,0.08 mmol, Sigma-Aldrich Corporation) andtrans-n,n′-dimethylcyclohexane-1,2-diamine (10.81 mg, 0.012 ml, 0.076mmol, Sigma-Aldrich Corporation) in 1,4-dioxane (0.950 ml). The reactionmixture w as stirred and irradiated in a Biotage microwave reactor at aset temperature of 130° C. for 5 min when LC/MS showed nearly fullconversion to desired product. The crude material was absorbed onto aplug of silica gel and purified by chromatography via a 10 g biotagecolumn ultra (gradient of 10% to 25% to 40% [3:1 EtOAc:EtOH]/Heptanewith 0.5% Et3N) to provide 20 mg of impure material which was furtherpurified by RP-HPLC (PREP LC/MS-2 System Column: XBridge Shield RP1819×100 mm 10 um Mobile phase: 0.1% NH4OH in water/acetonitrile Flowrate: 40 ml/min Gradient: 10 min 20-50%) to provide 19-1. m/z: 450.0[M+1]. ¹H NMR (DMSO-d6) δ: 10.68-10.74 (m, 1H), 9.14 (s, 1H), 8.82-8.87(m, 1H), 8.53 (s, 1H), 8.02 (s, 1H), 7.93-8.00 (m, 2H), 7.67-7.71 (m,1H), 4.26-4.33 (m, 2H), 4.17 (t, J=4.8 Hz, 1H), 2.11-2.36 (m, 4H),2.00-2.10 (m, 1H), 1.80-1.87 (m, 1H), 1.70-1.79 (m, 1H), 1.61 (ddd,J=12.1, 8.9, 3.6 Hz, 1H), 1.41 (dd, J=12.7, 4.0 Hz, 1H) Method 20;

Example 20-1:N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-7-(4-methylpyrimidin-2-yl)-1H-indole-3-carboxamide

Intermediate C-3 (0.1 g, 0.28 mmol) was treated with borylation andSuzuki reaction conditions used for the synthesis of Intermediate K andpurified via RP-HPLC (PREP LC/MS-2 System Column: XBridge Shield RP1819×100 mm 10 um Mobile phase: 0.1% NH4OH in water/acetonitrile Flowrate: 40 ml/min Gradient: 10 min 20-50%) to provide 20-1 as a whitesolid (0.006 g, 5% yield), m/z: 373.0 [M+1] ¹H NMR (DMSO-d6) δ: 8.83 (d,J=5.1 Hz, 1H), 8.35 (br t, J=6.6 Hz, 2H), 8.23 (brd, J=2.8 Hz, 1H),8.14-8.21 (m, 1H), 7.34 (d, J=5.0 Hz, 1H), 7.28 (t, J=7.7 Hz, 1H),4.31-4.40 (m, 1H), 4.27 (s, 1H), 4.16 (s, 1H), 4.03-4.12 (m, 1H), 2.65(s, 3H), 2.17-2.30 (m, 1H), 1.90-2.00 (m, 1H), 1.78-1.88 (m, 1H), 1.70(br s, 2H), 1.53 (br dd, J=12.7, 4.7 Hz, 1H)

Method 21:

Example 21-1-1-21-1-4

Intermediate E-10 (0.15 g, 0.58 mmol) was treated with amidationconditions described in Method 1. The sample was purified by SFC using aChiralpak AD-H 2×15 cm, 5 um column, a mobile phase of 50% methanolusing a flow rate of 80 mL/min. to generate 12 mg of peak 1 and 2 and 23mg of peak 3 with an ee of >99% and 19 mg of peak 4 with an ee of >99%.Peak 1 and 2 was purified by SFC using a Chiralpak AD-H 2×25 cm 5 urncolumn, a mobile phase of 30% methanol using a flowrate of 80 mL/min togenerate 3 mg of peak 1 with an ee of >99% and 1 mg of peak 2 with an eeof >98%. Peak assignment determined by SFC: Chiralpak AD-H, 30% and 50%methanol and stereochemistry was arbitrarily assigned, m/z: 377.0 [M+1]¹H NMR: see analytical data table.

Method 22:

Example 22-1:N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-<6-methyl-2-pyridinyl)-7-(trifluoromethyl)-1H-indazole-5-carboxamide

Methyl 7-(trifluoromethyl)-1H-indazole-5-carboxylate (0.08 g, 0.328mmol, synnovator) was treated with conditions described in Method 19 toobtain methyl1-(6-methylpyridin-2-yl)-7-(trifluoromethyl)-1H-indazole-5-carboxylate(0.1 g, 91% yield) after silica gel chromatography (10 g biotage ultracolumn, 10%-60% [EtOAc/EtOH (3/1)]:Heptane. This material was treatedwith conditions described in method 13 to obtain the final compound,m/z: 441.0 [M+1]. ¹H NMR (DMSO-d6) δ: 9.61 (s, 1H), 8.85 (d, J=5.8 Hz,1H), 8.74 (s, 1H), 8.19 (s, 1H), 8.01-8.08 (m, 2H), 7.46 (d, J=7.3 Hz,1H), 4.31-4.36 (m, 1H), 4.29 (t, J=4.4 Hz, 1H), 4.19 (t, J=4.9 Hz, 1H),2.62 (s, 3H), 2.21-2.30 (m, 1H), 1.89-1.96 (m, 1H), 1.80-1.89 (m, 1H),1.66-1.76 (m, 2H), 1.59 (dd, J=12.7, 4.6 Hz, 1H)

Method 23:

Example 23-1:1-((1R,2R,4S)-7-Cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2,5-dichlorophenethyl)urea

The mixture of Intermediate A (8.1 mg, 0.047 mmol), CDI (11 mg, 0.068mmol), DIEA (0.030 mL, 0.17 mmol) DMF (0.3 mL) was stirred at roomtemperature for 30 min After adding 2-(2,5-dichlorophenyl)ethan-1-amine(19 mg, 0.10 mmol) at room temperature, the mixture was stirred for 16 hand purified by preparative HPLC (0.1% AcOH) to afford the desiredproduct (15 mg, 90%) as a white solid after lyophilization. MS (EI) forC₁₆H₁₈Cl₂N₄O, found 353.3 [M+1].

Method 24:

Example 24-1:N1-(((3R,5R,7R)-Adamantan-1-yl)methyl)-N2-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N1-(2-hydroxyethyl)oxalamide

To a stirred solution of Intermediate A (9.0 mg, 0.052 mmol), diphenyloxalate (15 mg, 0.062 mmol) and dichloromethane (0.5 mL) was added DIEA(0.0.30 mL, 0.17 mmol) at room temperature. After stirring for 1 h, theresulting mixture was concentrated and brought up in DMF (0.5 mL). Afteradding 2-((((3r,5r,7r)-adamantan-1-yl)methyl)amino)ethan-1-ol (HCl salt,27 mg, 0.11 mmol) and DIPEA (0.030 mL, 0.17 mmol) at room temperature,the mixture was stirred for 3 h and purified by preparative HPLC (0.1%AcOH) to afford the desired product (13 mg, 62%) as a white solid afterlyophilization. MS (ESI)=401.3 [M+1].

Method 25:

Example 25-1:2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4-ethyl-1H-pyrazol-1-yl)benzamide

4-bromo-2-chloro-N-((1R,2R,4S)-7-<4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)benzamide(100 g, 0.222 mmol) was treated with conditions described in Method 19to obtain2-chloro-4-(4-ethyl-1H-pyrazol-1-yl)-N-((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)benzamideafter silica gel chromatography (10 g biotage ultra column, 10%-50%[EtOAc/Heptane]. This material was treated with conditions of method 15to obtain the final compound. m/z: 410.0 [M+1]. ¹H NMR (500 MHz,CHLOROFORM-d) δ ppm 0.90 (t, J=6.94 Hz, 4H) 1.18 (dd, J=12.98, 4.41 Hz,5H) 1.25-1.34 (m, 9H) 1.60-1.66 (m, 5H) 1.96-2.15 (m, 15H) 2.55-2.61 (m,5H) 4.11-4.14 (m, 5H) 4.49-4.52 (m, 4H) 4.53-4.59 (m, 5H) 4.89 (q,J=8.56 Hz, 9H) 6.53 (br d, J=5.71 Hz, 4H) 6.92 (d, J=8.30 Hz, 4H) 7.27(s, 1H) 7.46 (d, J=7.53 Hz, 5H) 7.77 (t, J=7.85 Hz, 5H) 7.86 (d, J=8.17Hz, 4H) 7.96 (dd, J=8.17, 1.69 Hz, 4H) 8.06 (d, J=1.69 Hz, 4H).

Method 26:

The synthesis was performed with Method 1,1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-oxopyrrolidine-3-carboxamidewas obtained in 70% yield.

The chiral separation was performed as follows: The sample was purifiedby SFC Chiralpak AD-H 2×15 cm 5 mic column, a mobile phase of 40%methanol using a flow rate of 80 mL/min. to generate 19.71 mg ofEnantiomer 1 peak 1 with an ee>99% and Enantiomer 2 17.52 mg of peak 2with an ee>99%. Peak assignment determined by SFC: Chiralpak AD-Hanalytical column, 40% methanol and stereochemistry was arbitrarilyassigned.

Method 27

The synthesis was performed with Method 13,N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyclopropylpyrimidin-2-yl)pyrrolidine-3-carboxamidewas obtained in 54% yield (45 mg).

The chiral separation was performed as followed. The sample was purifiedby SFC using a Chiralpak AD-H 2×25 cm, 5 um column, a mobile phase of35% methanol using a flowrate of 80 mL/min. to generate 6.9 mg of peak 1with an ee>99% and 7.89 mg of peak 2 with an ee>99%. Peak assignmentdetermined by SFC: Chiralpak AD-H analytical column, 35% methanol andstereochemistry was arbitrarily assigned.

Method 28:

Step 1: To the solution of (S)-1-boc-pyrrolidine-3-carboxylic acid (215mg, 1 mmol, Combi-Blocks) and hatu (418 mg, 1.100 mmol, Combi-BlocksInc.) in N,N-dimethylformamide (2500 μl) was addedn,n-diisopropylethylamine (646 mg, 5.00 mmol) dropwise at roomtemperature. The solution turned yellow. LS-MS at 1 h showed thecompletion of the reaction. The solution was poured into sat. NaHCO3 (10mL) (lots of white precipitates) and extracted with EtOAc (30 mL×2). Theorganic extracts were combined and washed with water (20 mL×2), brine,dried over Na2SO4 and concentrated. To the crude mixture was added HClin Dioxane (2.5 mL, 4N) and the mixture was stirred for 1 h. LC-MSshowed the completion of the reaction. The solvent was removed, and thematerial was brought up in MeOH, passed through an SCX-2 column (5 g)washing with MeOH (3 CV). The column was washed with ammonia in MeOH toelute the pure amine product which was used directly in the C—N couplingstep.

Step 2: To a 2 dram vialcontaining(S)-N-((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)pyrrolidine-3-carboxamide(61.5 mg, 0.187 mmol, 125374-7-2) was added ruphos, 95% (2.178 mg, 4.67μmol) and Ruphos Pd G1 (3.40 mg, 4.67 μmol) The mixture was degassed andfilled with N2 three times before 1,1,1,3,3,3-hexamethyldisilazanelithium salt (560 μl, 0.560 mmol) in THF (1M) was added, followed by1,3,5-trichlorobenzene (102 mg, 0.560 mmol). The mixture was sonicatedand heated at 70° C. LC-MS after 1 h showed complete conversion to theproduct. The crude mixture was used directly in the following step.

Step 3: Water (8.41 mg, 8.41 μl, 0.467 mmol, Lab) was added dropwise toquench the reaction potassium carbonate (77 mg, 0.560 mmol) was thenadded followed by cyanogen bromide solution, 5.0 m in acetonitrile (74.7μl, 0.373 mmol). The mixture was then stirred at room temperatureovernight. After the reaction the mixture was quenched with water,extracted with DCM, concentrated and applied to a column (0%-80% EA inHeptane) to afford(S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)pyrrolidine-3-carboxamidein 11% yield.

Method 29:

A 2 dram vial containing(S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)pyrrolidine-3-carboxamidehydrochloride (0.2 mmol) was added6-chloro-4-(trifluoromethyl)picolinonitrile (62.0 mg, 0.300 mmol),acetonitrile (667 μl) and DIPEA (140 μl, 0.800 mmol). The suspension wasstirred at 60° C. for 2 h when LC-MS showed good conversion (80%). Thereaction was purified via RP-HPLC with 0.1% NH4OH in ACN and water asmobile phase to afford(S)-1-(6-cyano-4-(trifluoromethyl)pyridin-2-yl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)pyrrolidine-3-carboxamidein 41% yield.

Method 30:

To a mixture of (S)-1-(m-tolyl)pyrrolidine-3-carboxylic acid (0.19 mmol)and n,n-diisopropylethylamine (98 mg, 133 μl, 0.759 mmol) in N,N-dimethylformamide (667 μl) was added COMU (89 mg, 0.209 mmol). Then(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonitrilehydrochloride (65.9 mg, 0.190 mmol) was added. The mixture was stirredat room temperature. After 1 h, the reaction was complete. The mixturewas poured into NaHCO3 (sat), extracted with EA (30 mL×2) and the EAlayers were combined, washed with water and brine, dried over Na2SO4 andconcentrated. The residue was purified by silica gel chromatography(0%-75% EA in Heptane) to afford(S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(m-tolyl)pyrrolidine-3-carboxamidein 29% yield.

Method 31:

Step 1: To the 8 mL vial containing 1H-pyrazole-4-carboxylic acid (0.3mmol) was added hatu (0.125 g, 0.330 mmol) and(1R,2R,4S)-2-amino-7-azabicyclo[2.2.1]heptane-7-carbonitrilehydrochloride (0.104 g, 0.300 mmol) in N,N-dimethylformamide (1.200 ml).Then DIPEA (0.155 g, 0.210 ml, 1.200 mmol) was added. The mixture wasstirred at room temperature. After 2 h the compound was purified byRP-HPLC (5%-50% ACN in water+0.1% formic acid) to afford the product,which was used directly in the Cu catalyzed C—N coupling step.

Step 2: To a 2 dram vial was addedN-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1H-pyrazole-4-carboxamide(0.3 mmol), copper(i) iodide, (0.03 mmol), cesium carbonate (0.6 mmol),3,5-dichloroiodobenzene (0.45 mmol),(1r,2r)-(−)-n,n″-dimethylcyclohexane-1,2-diamine (8.53 mg, 9.46 μl,0.060 mmol) and DMF (600 μl). The mixture was stirred at 100° C. for 1h, was purified directly via RP-HPLC with 0.1% NH4OH in ACN and water asmobile phase to affordN-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-1H-pyrazole-4-carboxamidein 4% yield.

Method 32:

Step 1: To a 2 dram vial was added 3-bromo-5-chlorobenzonitrile (0.25mmol), potassium carbonate (111 mg, 0.800 mmol), tris(dibenzylideneacetone) dipalladium (0) (0.013 mmol) and2,2′-bis(diphenylphosphaneyl)-1,1′-binaphthalene (0.026 mmol). The vialwas evacuated and back filled with N2 two times. Then(S)-N-((1R,2R,4S)-7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptan-2-yl)pyrrolidine-3-carboxamide(500 μl, 0.25 mmol) in THF was added. The dark red solution was stirredat 70° C. for 20 h. LC-MS showed good conversion to the product.

Step 2: Cyanogen bromide solution, 5.0 m in acetonitrile (150 μl, 0.750mmol) was directly added to the reaction mixture. The mixture wasfurther stirred for 30 min. LC-MS showed full conversion to thecyanamide. The reaction was quenched with water and extracted with DCM(5 mL×3). The combined DCM lay ers were concentrated and the residue waspurified by silica gel chromatography (0-100% EA in Heptane) to affordthe product(S)-1-(3-chloro-5-cyanophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)pyrrolidine-3-carboxamidein 30% yield.

Method 33:

The synthesis followed the procedure in Method 23 followed by SFCpurification Column: Zorbax Eclipse Plus C18 5 um 21.2×100 mm MobilePhase: Solvent A=0.1% Formic Acid in 100% Water. Solvent B=AcetonitrileGradient: Start % B=47.3 Final % B=67.3 Gradient. Time=7 min, then a 2min hold at 98% B. Wavelength=215 and 254 nm. ESI+Range: 150 to 1500dalton. Sample was loaded at 25% B. Flow Rate: 40.0 mL/min Sample: 300mg of sample was dissolved in 4 mL DMSO Inj: 0.5 mL Peak1, 8.2 mg Peak2,19.2 mg Step 2: Peak 2, the major diastereomer, was further separatedinto two enantiomers: Sample was purified via preparative SFC using aChiral Technologies IC (250×21 mm, 5 mm) with a mobile phase of 75%Liquid CO2 and 75% MeOH using a flowrate of 90 mL/min. to generate 7 mgof peak 1 with an ee of >99% and 4 mg of peak 2 with an ee of >99%. Peakassignment determined by SFC with IC column with 25% MeOH andstereochemistry was arbitrarily assigned.

Table of Examples and Analytical Data

The compounds below were synthesized using the methods above and areclassified using the numbering convention detailed in the syntheticexample section.

Ex # Name Structure 1-1 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(1H-pyrrol--1-yl)-1,3-benzethiazol-6-carboxamide

1-2 racemic-endo 2-methyl-2-propanyl 7-(7-cyano-7-azabicyclo[2.2.1]heptan-2- yl)carbamoyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate

1-3 racemic-endo 2-methyl-2-propanyl 6-(7-cyano-7-azabicyclo[2.2.1]heptan-2- yl)carbamoyl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate

1-4 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-((4-cyclopropyl-2-pyrimidinyl)amino)-2,5- difluorobenzamide

1-5 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-((4-cyclopropyl-2-pyrimidinyl)amino)-2,3- difluorobenzamide

1-6 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-phenyl-1H-indazole-6-carboxamide

1-7 2-methyl-2-propanyl (4-(((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-methylphenyl)carbamate

1-8 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(2,2-dimethylpropanoyl)-2,3-dihydro-1H-indole- 5-carboxamide

1-9 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1,3-thiazol- 4-yl)benzamide

1-10 4-benzamido-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)benzamide

1-11 N-(4--(((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)carbamoyl)phenyl)-2- pyridinecarboxamide

1-12 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(phenylethynyl)benzamide

1-13 6-(1H-benzimidazol-1-yl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3- pyridinecarboxamide

1-14 4-((5-chloro-2-pyridinyl)oxy)-N- ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)benzamide

1-15 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(3,5-dimethyl-1H-pyrazol-1-yl)-3- fluorobenzamide

1-16 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1,1-dioxido-1,2-thiazolidin-2-yl)benzamide

1-17 2-methyl-2-propanyl (3-chloro-4- (((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2- yl)carbamoyl)phenyl)carbamate

1-18 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-4-(3- methylbutanamido)benzamide

1-19 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(4-methyl-1H-pyrazol-1-yl)benzamide

1-20 4-(1H-benzotriazol-1-yl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2- yl)benzamide

1-21 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(4-pyridinyl)benzamide

1-22 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-6-(cyclopropylmethoxy)-3- pyridinecarboxamide

1-23 4-(3-chloro-2-pyridinyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2- yl)benzamide

1-24 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(3-pyridinyl)benzamide

1-25 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(3-methyl-1H-pyrazol-1-yl)benzamide

1-26 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(4-(triftuoromethyl)-1H-pyrazol-1-yl)benzamide

1-27 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(3-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)benzamide

1-28 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4-methyl- 1H-pyrazol-1-yl)benzamide

1-29 N((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzamide

1-30 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-methyl-4-(4-methyl-1H-pyrazol-1-yl)benzamide

1-31 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-fluoro-4-(4-methyl-1H-pyrazol-1-yl)benzamide

1-32 racemic-endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-5-(4-fluorophenyl)-2-pyridinecarboxamide

1-33 racemic-endo 6-(4-chlorophenyl)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3- pyridinecarboxamide

1-34 6-(4-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3- pyridinecarboxamide

1-35 racemic-endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-(3-methylanilino)-5- pyridinecarboxamide

1-36 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyridinyl)-6-fluoro-1H- indazole-5-carboxamide

1-37 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyano-6-methyl-2-pyridinyl)-1H- indazole-5-carboxamide

1-38 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-2-pyridinyl)-1H- pyrrolo[2,3-b]pyridine-5- carboxamide

1-39 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-1,3-thiazol-2-yl)-1H-indazole-5-carboxamide

1-40 Mixture of two diastereomers: (S)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-methyl-2-pyridinyl)-4,5,6,7-tetrahydro-1H- indazole-5-carboxamide and(R)-N-(7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-methyl-2-pyridinyl)-4,5,6,7-tetrahydro-1H- indazole-5-carboxamide

and

1-41 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(4-methyl-2-pyridinyl)-1H- indole-6-carboxamide

1-42 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-6-methoxy-1-(4-methyl-2-pyrimidinyl)-1H- indole-5-carboxamide

1-43 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-methyl-3-(6-methyl-2-pyridinyl)-1H- indazole-6-carboxamide

1-44 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-methyl-3-(6-(trifluroromethyl)-2-pyridinyl)-1H- indazole-6-carboxamide

1-45 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-methyl-3-phenyl-1H-indazole-6-carboxamide

1-46 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-((3-fluorophenoxy)methyl)benzamide

1-47 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(2-thiophenylmethoxy)benzamide

1-48 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-((2-methylphenyl)sulfanyl)benzamide

1-49 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(3-methylbutoxy)benzamide

1-50 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-((2-cyanophenyl)sulfanyl)benzamide

1-51 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyridinyl)-3-methyl-1H- indazole-5-carboxamide

1-52 6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6- cyclopropyl-2-pyridinyl)-1H-indazole-5-carboxamide

1-53 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyridinyl)-6-methyl-1H- indazole-5-carboxamide

1-54 5-bromo-3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-methyl-1H- indole-2-carboxamide

1-55 Mixture of two diastereomers: (2R)-5-bromo-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)- 2,3-dihydro-1H-indene-2-carboxamide, and(2S)-5-bromo-N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2,3-dihydro-1H-indene-2-carboxamide

and

1-56 5-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1- benzothiophene-2-carboxamide

1-57 N-benzyl-3-bromo-N-(2-(((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2- yl)amino)-2-oxoethyl)benzamide

1-58 N-benzyl-3-chloro-N-(2-(((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2- yl)amino)-2-oxoethyl)benzamide

1-59 3-bromo-N-(2-(((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)amino)-2- oxoethyl)benzamide

1-60 3-chloro-N-(2-(((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)amino)-2- oxoethyl)benzamide

1-61 Mixture of two diastereomers: (3R)-1-(3-chlorophenyl)-N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-5-oxo-3-pyrrolidinecarboxamide, and (3S)-1-(3- chlorophenyl)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-oxo-3- pyrrolidinecarboxamide

and

1-62 Mixture of two diastereomers: (3R)-1-(3- bromophenyl)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-oxo-3- pyrrolidinecarboxamide, and(3S)-1-(3- bromophenyl)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-oxo-3- pyrrolidinecarboxamide

and

1-63 Mixture of two diastereomers: (3R)-1-(3-chlorophenyl)-N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-oxo-3-pyrrolidinecarboxamide, and (3S)-1-(3- chlorophenyl)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-oxo-3- pyrrolidinecarboxamide

and

1-64 2-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1,3-thiazole- 4-carboxamide

2-1-1 2-(4-chloro-3-(trifltioromethyl)phenoxy)-N-((endo)-7-cyano-7-azabicyclo[2.2.1]heptan- 2-yl)acetamide enantiomer 1

2-1-2 2-(4-chloro-3-(trifltioromethyl)phenoxy)-N-((endo)-7-cyano-7-azabicyclo[2.2.1]heptan- 2-yl)acetamide enantiomer 2

3-1-1 3-(3-chlorophenyl)-N-(endo)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1,2-oxazole-5- carboxamide enantiomer 1

3-1-2 3-(3-chlorophenyl)-N-((endo)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1,2-oxazole-5- carboxamide enantiomer 2

3-3 Racemic, endo 2-((4-chloro-3-(trifltioromethyl)phenyl)amino)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide

3-7 Racemic, endo 3-bromo-N-(1-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)amino)-1- oxopropan-2-yl)benzamide

3-8 Racemic, endo 3-bromo-N-(1-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)amino)-2- methyl-1-oxopropan-2-yl)benzamide

4-1-1 (endo)-7-cyano-N-(4-(3-(trifltuoromethyl)phenyl)-1,3-thiazol-2-yl)-7-azabicyclo[2.2.1]heptan-2-carboxamide

4-1-2 (endo)-7-cyano-N-(4-(3-(trifluoromethyl)phenyl)-1,3-thiazol-2-yl)-7-azabicyclo[2.2.1]heptan-2-carboxamide

4-1-3 (exo)-7-cyano-N-(4-(3-(trifluoromethyl)phenyl)-1,3-thiazol-2-yl)-7-azabicyclo[2.2.1]heptan-2-carboxamide

4-1-4 (exo)-7-cyano-N-(4-(3-(trifluoromethyl)phenyl)-1,3-thiazol-2-yl)-7-azabicyclo[2.2.1]heptan-2-carboxamide

4-2-1 (endo)-2-((5-(2-fluoro-5-methylphenyl)-2,3-dihydro-1H-indol-1-yl)carbonyl)-7-azabicyclo[2.2.1]heptan-7-carbonitrile

4-2-2 (endo)-2-((5-(2-fluoro-5-methylphenyl)-2,3-dihydro-1H-indol-1-yl)carbonyl)-7-azabicyclo[2.2.1]heptane-7-carbonitrile

4-2-3 (exo)-2-((5-(2-fluoro-5-methylphenyl)-2,3-dihydro-1H-indol-1-yl)carbonyl)-7-azabicyclo[2.2.1]heptane-7-carbonitrile

4-2-4 (exo)-2-((5-(2-fluoro-5-methylphenyl)-2,3-dihydro-1H-indol-1-yl)carbonyl)-7-azabicyclo[2.2.1]heptane-7-carbonitrile

5-1 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4,6-dimethyl-2-pyrimidinyl)-2,3-dihydro-1H- indole-5-carboxamide

5-2 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyridinyl)-2,3-dihydro-1H- indole-5-carboxamide

5-3 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyrazinyl)-2,3-dihydro-1H- indole-5-carboxamide

5-4 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(3-cyclopropylphenyl)-2,3-dihydro-1H- indole-5-carboxamide

5-5 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyclopropyl-2-pyridinyl)-2,3-dihydro-1H- indole-5-carboxamide

5-6 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4-methoxy-2-pyrimidinyl)-2,3-dihydro-1H- indole-5-carboxamide

5-7 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4-(trifluoromethyl)-2-pyrimidinyl)-2,3-dihydro-1H- indole-5-carboxamide

5-8 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4-(2-methyl)-2-propanyl)-2-pyrimidinyl)-2,3- dihydro-1H-indole-5-carboxamide

5-9 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4-(2-propanyl)-2-pyrimidinyl)-2,3- dihydro-1H-indole-5-carboxamide

5-10 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-ethyl-2- pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide

5-11 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyano-2- pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide

5-12 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyano-6- methyl-2-pyrimidinyl)-2,3-dihydro-1H-indole-5-carboxamide

5-13 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4-(difluoromethyl)-2-pyrimidinyl)-2,3- dihydro-1H-indole-5-carboxamide

5-14 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-6-(trifluoromethyl)-2-pyrimidinyl)-2,3- dihydro-1H-indole-5-carboxamide

5-15 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3-fluoro-6- methyl-2-pyridinyl)-2,3-dihydro-1H-indole-5-carboxamide

6-1 Racemic, endo N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-2-pyrimidinyl)-1H-indole-5-carboxamide

6-2 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(2-pyrimidinyl)-2,3-dihydro-1H-indole-5- carboxamide

6-3 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(5-methyl-2-pyrimidinyl)-2,3-dihydro- 1H-indole-5-carboxamide

7-1 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyclopropyl-2-pyrimidinyl)-N- methyl-2,3-dihydro-1H-indole-5-carboxamide

7-2 N-((1S,2S,4R)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyclopropyl-2-pyrimidinyl)-N- methyl-2,3-dihydro-1H-indole-5-carboxamide (peak 2 derived)

8-1 Racemic, endo N~5~-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-N~1~-cyclopropyl-2,3-dihydro- !H-indole-1,5-dicarboxamide

8-2 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(4-(trifluoromethyl)phenyl)urea

9-1 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzamide

9-2 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(cyclopropylmethoxy)- 4-(1-methyl-1H-pyrazol-4-yl)benzamide

9-3 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-pyrazol-4-yl)propoxybenzamide

9-4 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)benzamide

9-5 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-pyrazol-4-yl)-3-(2- propanyloxy)benzamide

9-6 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)benzamide

9-7 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-pyrazol-4-yl)-3- (trifluoromethoxy)benzamide

9-8 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-pyrazol-4-yl)-3- (trifluoromethyl)benzamide

9-9 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(6-(trifluoromethyl)-2-pyridinyl)-1H-indazole 6-carboxamide

10-1 Racemic, endo 2-((3- bromobenzyl)(methyl)amino)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide

11-1 Racemic, endo 2-(4-chloro-2- cyclohexylphenoxy)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide

11-2 N~2~-benzyl-N~2~-(3-bromobenzyl)-N- ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl) glycinamide

11-3 N~2~-benzyl-N~2~-(3-chlorobenzyl)-N- ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl) glycinamide

11-4 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-(5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4- ylsulfanyl)acetamide

11-5 N~2~-(3-bromobenzyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)- N~2~-(2-methylpropyl)glycinamide

11-6 N~2~-(3-chlorobenzyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)- N~2~-(2-methoxybenzyl)glycinamide

11-7 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-(5,7-dichloro-3,4-dihydro-2(1H)- isoquinolinyl)acetamide

11-8 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-(2,4-dichloro-5-ethyl-3-methylphenoxy)acetamide

11-9 Racemic, endo 2-((5-chlorobenzo[d]thiazol- 2-yl)thio)-N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)acetamide

12-1 Racemic, endo 2-(4-((4- chlorophenyl)thio)piperdine-1-carbonyl)-7-azabicyclo[2.2.1]heptan-7-carbonitrile

13-1 Racemic, endo N-(7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-2-pyrimidinyl)-2,3-dihydro-1H-indole-5- carboxamide

13-2 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(cyclopropylcarbonyl)-2,3-dihydro-1H-indole-5- carboxamide

13-3 6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-methyl-2-pyridinyl)-1H-indole-5-carboxamide

13-4 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-methyl-2-pyridinyl)-1H- indole-5-carboxamide

13-5 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-6-fluoro-1-(6-methyl-2-pyridinyl)-1H- indole-5-carboxamide

13-6 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(4-cyclopropyl-2-pyrimidinyl)- 3,4-dihydro-2H-indole-1,4-benzoxazine-7-carboxamide

13-7 2-((4-chloro-1-naphthalenyl)oxy-N- ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-acetamide

13-8 2-((4-chloro-1-naphthalenyl)oxy-N- ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-acetamide (peak 2 derived)

13-9 Racemic, endo 2-methyl-2-propanyl 5-((7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-carbamoyl)-2,3-dihydro-1H-indole-1- carboxylate

13-10 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-2-pyrimidinyl)-1H- benzimidazole-5- carboxamide

13-11 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-2-pyrimidinyl)-1H-indazole-5- carboxamide

13-12 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyclopropyl-2-pyridinyl)-1H-indazole- 5-carboxamide

13-13 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyridinyl)-1H-indazole- 5-carboxamide

13-14 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyridinyl)-1H- indazole-5-carboxamide

13-15 3-(4-chloro-3-(trifluoromethyl)phenyl)-N- ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)propanamide

13-16 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-ethyl-2-pyridinyl)-1H-indazole-5- carboxamide

13-17 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-2-pyrimidinyl)-1H-pyrrolo [3,2-b]pyridine-5-carboxamide

13-18 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-fluoro-1-(4-methyl-2-pyrimidinyl)-1H-indole-5- carboxamide

13-19 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(methyl(4-methyl-2-pyrimidinyl) amino)benzamide

13-20 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-methyl-1-(4-methyl-2-pyrimidinyl)-1H-indole-5- carboxamide

14-1 Racemic, endo N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(2-pyrimidinylamino)benzamide

14-2 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-6-(3,5-dimethyl-1-(2-oxazol-4-yl)-1H-indole-2- carboxamide

14-3 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4,cyclopropyl-2-pyrimidinyl)- 2,3-dihydro-1H-indole-5- carboxylate

14-4 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4,cyclopropyl-2-pyrimidinyl)- 2,3-dihydro-1H-indole-5- carboxylate

14-5 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl-1H-pyrazole-4-yl)benzamide

15-1 6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-2-pyrimidinyl)-2,3-dihydro-1H-indole-5- carboxamide

16-1 5-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-methyl- 1,3-thiazole-2-carboxamide

16-2 5-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)- 1,3-thiazole-2-carboxamide

1-65 2-chloro-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-((cyclopropylcarbonyl)amino)benzamide

1-66 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1H-indazol- 1-yl)benzamide

1-68-2 (3S)-6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

1-69 (4R)-7-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3,4,5-tetrahydro-1-benzoxepine-4-carboxamide

1-70 5-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-methyl-3-(6-methyl-2-pyridinyl)-1H-indazole-6- carboxamide

1-71 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(cyclopropylmethyl)-3-(6-methyl-2- pyridinyl)-1H-indazole-6- carboxamide

1-72 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(2-methylpropyl)-3-(6-methyl-2-pyridinyl)-1H- indazole-6-carboxamide

1-73 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(6-methyl-2-pyridinyl)-1- (4,4,4-trifluorobutyl)-1H- indazole-6-carboxamide

1-74 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(6-methyl-2-pyridinyl)-1-propyl-1H- indazole-6-carboxamide

1-75 6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(2,2,2-trifluoroethoxy)-2-pyridinyl)-1H- indazole-5-carboxamide

1-76 6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(7- naphthtyridin-2-yl)-1H-indazole-5-carboxamide

1-77 6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6- (cyanomethyl)-2-pyridinyl)-1H-indazole-5-carboxamide

1-78 6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(1,8- naphthtyridin-2-yl)-1H-indole-5-carboxamide

1-79 4-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1,3-thiazole- 2-carboxamide

1-80 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-(3-thiophenyl)-1,3-thiazole-4-carboxamide

1-81 1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1H-pyrazole- 3-carboxamide

1-82 1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-methyl- 1H-pyrazole-3-carboxamide

1-83 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(2-methyl-1,3-thiazole-4-carboxamide

1-84 7-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxamide

1-85 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-phenyl-3-pyrrolidinecarboxamide

1-86 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-methyl-1-phenyl-3-pyrrolidinecarboxamide

1-87 (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyano-2-fluorophenyl)-3-pyrrolidinecarboxamide

1-88 1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3- pyrrolidinecarboxamide

1-89 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-5-phenyl-2-furancarboxamide

1-90 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-5-(3-(2-propanyl)phenyl-2- furancarboxamide

1-91 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-5-(3-(trifluoromethyl)phenyl-2- furancarboxamide

1-92 1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3- piperidinecarboxamide

1-93 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4-(trifluoromethyl)-2-pyrimidinyl)-4- piperidinecarboxamide

1-94 1-(3-bromophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3- pyrrolidinecarboxamide

1-95 1-(3-chloro-4-(trifluoromethyl)phenyl-N- ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3- pyrrolidinecarboxamide

1-96 6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-yl)-3,4-dihydro-2H-chromene-3-carboxamide

1-97 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6- cyclopropyl-2-pyridinyl)benzamide

2-2 1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4- piperidinecarboxamide

2-3 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-4-piperidinecarboxamide

2-4 (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-2-pyridinyl)-3-pyrrolidinecarboxamide

2-5 (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(5-cyano-3-pyridinyl)-3-pyrrolidinecarboxamide

2-6 (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(2-methoxy-4-pyridinyl)-3-pyrrolidinecarboxamide

2-7 (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-methyl-2-pyridinyl)-3-pyrrolidinecarboxamide

2-8 (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-methoxy-2-pyridinyl)-3-pyrrolidinecarboxamide

2-9 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-3-methyl-3- pyrrolidinecarboxamide

2-10 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-3-fluoro-3- pyrrolidinecarboxamide

2-11 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-(3,5-dichlorophenyl)-2-azabicyclo[3.1.0]hexane-4- carboxamide

2-12 2-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1,3-oxazole- 5-carboxamide

2-13 (3S)-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(3-(cyanomethyl)phenyl)-3- pyrrolidinecarboxamide

2-14 (3S)-1-(3-chloro-5-methoxyphenyl)- N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-3- pyrrolidinecarboxamide

2-15 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-L-prolinamide

2-16 3′-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)[biphenyl]-3- carboxamide

2-17 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(2,5-dichlorophenyl)-5-methyl-2- pyridinecarboxamide

2-18 4-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-methyl-2- pyridinecarboxamide

2-19 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-(1-cyanocyclopropyl)-2-pyridinyl)-4- piperidinecarboxamide

2-20 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-6-(3-(1-cyanocyclopropyl)phenyl)-3- pyridinecarboxamide

2-21 3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-cyclopropyl-5′-fluoro[biphenyl]-4-carboxamide

2-22 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-6-(1-cyanocyclopropyl)[2,3′-bipyridine]-6′- carboxamide

2-23 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1-ethnylcyclopropyl-2-pyridinyl)benzamide

2-24-1 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3R)-3-cyano-3-methyl-2,3-dihydro-1H-inden-5- yl)benzamide

2-24-2 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3S)-3-cyano-3-methyl-2,3-dihydro-1H-inden-5- yl)benzamide

2-26 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-2-methyl-2-propanyl)-2-pyridinyl)benzamide

2-27-2 (1S,6R,7R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(3,5-dichlorophenyl)-3-azabicyclo[4.1.0]heptane- 7-carboxamide

2-27-1 (1R,6S,7R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(3,5-dichlorophenyl)-3-azabicyclo[4.1.0]heptane- 7-carboxamide

2-29 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(3,5-dichlorophenyl)-3-azabicyclo[4.1.0]heptane- 7-carboxamide

2-30 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyridinyl)-3- piperidinecarboxamide

2-31-2 (1S,5S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(3,5-dichlorophenyl)-3-azabicyclo[3.1.0] hexane-1-carboxamide

2-31-2 (1R,5R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(3,5-dichlorophenyl)-3-azabicyclo[3.1.0]hexane- 1-carboxamide

2-33 (1R,5S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(3,5-dichlorophenyl)-3-azabicyclo[3.1.0]hexane- 1-carboxamide

2-34 (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(1- cyanocyclopropyl)-2-pyridinyl)-3-piperidinecarboxamide

2-35 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-cyclopentyl- 1H-indazole-3-carboxamide

2-36 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl-2-pyridinyl)-4- piperidinecarboxamide

2-37 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3- carboxamide

2-38 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6- (2-cyano-propyl)-2-pyrazinyl)benzamide

2-39-1 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3S)-3- cyano-1-piperidinyl)benzamide

2-39-2 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3R)-3- cyano-1-piperidinyl)benzamide

2-41 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3S)-3- cyano-1-piperidinyl)benzamide

2-42 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3R)-3-cyano-3-methyl-2,3-dihydro-1H-inden-5- yl)benzamide

2-43-1 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((1S,2S,5R)-2-cyano-6-azabicyclo[3.2.1]octan-6- yl)benzamide

2-44 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(3-cyanophenyl)-1H-pyrazole-3-carboxamide

2-45 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1-cyanocyclobutyl)-2-pyridinyl)benzamide

2-46-2 (2S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-3,5-dichlorobenzyl)-2-azetidinecarboxamide

2-46-3 (2R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-3,5-dichlorobenzyl)-2-azetidinecarboxamide

2-48-1 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3S)-3-(cyanomethyl)-1-pyrrolidinyl)benzamide

2-48-2 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3R)-3-(cyanomethyl)-1-pyrrolidinyl)benzamide

2-50 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(3-cyanophenyl)-1H-indazole-3-carboxamide

2-51 (3R)-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorobenzyl)-3-pyrrolidinecarboxamide

2-52 (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(1- cyanocyclopropyl)-2-pyridinyl)-3-pyrrolidinecarboxamide

2-43-2 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((2R)-2-cyano-6-azabicyclo[3.2.1]octan-6- yl)benzamide

2-54 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((1- cyanocyclopropyl)methoxy)benzamide

2-55 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1-cyanocyclopropyl)-2-pyridinyl)-2- cyclopropylbenzamide

2-56 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-((cis-3- cyanocyclobutyl)oxy)benzamide

2-57 2-chloro-N-((1S,2R,4R)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3R)-3-cyanomethyl)-1-pyrrolidinyl)benzamide

2-58 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((cis-3- cyanocyclobutyl)oxy)benzamide

2-59 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1-cyano- 3,3-difluorocyclobutyl)-3-pyridinyl)benzamide

2-60 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-(1-cyanocyclopropyl)[biphenyl]-3-carboxamide

2-61-2 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3S)-3-cyanomethyl)-1-piperidinyl)benzamide

2-61-1 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3R)-3-(cyanomethyl)-1-piperidinyl)benzamide

2-63 3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-(1-cyanocyclopropyl)-5′-fluoro[biphenyl]- 4-carboxamide

2-64 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide

2-65 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(5,6- dihydrocyclopenta[c]pyrazol-1(4H)-yl)benzamide

2-66 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(5,6- dihydrocyclopenta[c]pyrazol-2(4H)-yl)benzamide

2-67 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-((3S)-3-cyanomethyl)-1-piperidinyl)benzamide

5-16 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-3-azepanecarboxamide

7-3 (3S)-6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N,9-dimethly-2,3,4,9-tetrahydro-1H-carbazole-3- carboxamide

7-4 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyclopropyl)-2-pyridinyl)-6-fluoro-N-methyl- 1H-indazol-5-carboxamide

7-5 6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N-methyl-1-(6-methyl-2-pyridinyl)-1H-indazol- 5-carboxamide

7-6 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-6-fluoro-N-methyl-1-(6-methyl-2-pyridinyl)-1H- indazol- 5-carboxamide

7-7 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-N,1-dimethyl-3-(6-methyl-2-pyridinyl)-1H- indazol- 6-carboxamide

7-8 (3R)-1-(3-chlorophenyl)- N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N- methyl-3-pyrrolidinecarboxamide

7-9 (3S)-1-(3-chlorophenyl)- N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N- methyl-3-pyrrolidinecarboxamide

7-10 (3R)-1-(3-chlorophenyl)- N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N- methyl-5-oxo-3-pyrrolidinecarboxamide

7-11 (3S)-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-N-methyl-3- pyrrolidinecarboxamide

7-12 (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3-cyano-6-(trifluoromethyl)-2-pyridinyl)-N-methyl-3- pyrrolidinecarboxamide

7-13-2 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N-methyl-1-(2,3,5-trichlorophenyl)-L-prolinamide

7-13-1 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N-methyl-1-(2,3,5-trichlorophenyl)-D-prolinamide

7-15 1-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(2-(2,5-dichlorophenyl)ethyl)-1,3-dimethylurea

7-16 1-(2-(2-bromo-5-chlorophenyl)ethyl)-3- ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1,3- dimethylurea

7-17 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1- cyanocyclopropyl)-2-pyridinyl)-N-methylbenzamide

7-18 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-N-methyl-3-(2-methylpropoxy)-4-(1-methyl-1H-pyrazol-4- yl)benzamide

9-1 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-methyl-4-(1-methyl-1H-pyrazol-4-yl)-1,3- benzothiazole-7-carboxamide

9-2 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-5-(2-methylpropoxy)-2,4-bis(1- methyl-1H-pyrazol-4-yl)benzamide

9-3 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-(2-methylpropoxy)-4-(1-methyl-1H-pyrazol-4- yl)benzamide

9-4 3-butoxy-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl- 1H-pyrazol-4-yl)benzamide

9-5 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(cyclobutylmethoxy)-4-(1-methyl-1H-pyrazol-4- yl)benzamide

9-6 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(1-methyl-1H-pyrazol-4- yl)benzamide

12-2 6-(5-azaspiro[2.5]octan-5-yl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4- pyrimidinecarboxamide

12-3 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-6-(2-methyl-2- phenyl-4-morpholinyl)-4-pyrimidinecarboxamide

12-4 6-(2-(4-chlorophenyl)-2-methyl-4-morpholinyl)-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-pyrimidinecarboxamide

12-5 6-(((1-(4- bromophenyl)cyclopropyl)methyl)(methyl)amino)-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-pyrimidinecarboxamide

12-6 2-chloro-N-(8-cyano-8- azabicyclo[3.2.1]octan-2-yl)-4-(4-methyl-1H-pyrazol-1-yl)benzamide

12-7 3-(6-chloro-2,3-dihydro-1H-indol-1-yl)-N- ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)propanamide

12-8 (2E)-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(2,5-dichlorophenyl)-2-methyl-2-butenamide

12-9 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(2,5-dichlorophenyl)butenamide

12-10 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(2,5-dichlorophenyl)cyclopentaneacarboxamide

12-11 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(4-fluorophenyl)benzamide

12-12 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(4-fluorobenzyl)benzamide

12-13 3-(4-chlorophenoxy)- N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl) benzamide

12-14 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-(dichlorobenzyl)cyclopropanecarboxamide

12-15 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(4-cyanophenoxy)benzamide

12-16 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-yl)dibenzo[b,d]furan-3-carboxamide

12-17 (2E)-3-(5-chloro-1-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2- propenamide

12-18 2-(3-bromo-2-cyanophenoxy)-N- ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)- acetamide

12-19 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)amino)-2-oxoethyl)-4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide

12-20 (3E)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(2,5-dichlorophenyl)-2-methoxy-3-butenamide

12-21 (3E)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(2,5-dichlorophenyl)-N-methoxy-3-butenamide

12-22 2′,5′-dichloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)[biphenyl]-3- carboxamide

12-23 (3E)-4-(3-chlorophenyl)- N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3- butenamide

12-24 (2E)-3-(5-chloro-1-ethyl-1H-indol-3-yl)-N- ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-methyl-2- propenamide

12-25 (3E)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(2,5- dichlorophenyl)-3-butenamide

12-26 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

12-27 (2E)-3-(5-chloro-1-benzothiophen-3-yl)-N- ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-methyl-2- propenamide

12-28 3′-bromo-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)[biphenyl]-3- carboxamide

12-29 (2E)-3-(5-chloro-1H-indazol-3-yl)-N- ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-methyl-2- propenamide

13-21 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-6-(4-methyl-2-pyrimidinyl)-1H-indole-2-carboxamide

13-22 5-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2- furancarboxamide

13-23 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyclopropyl-2-pyrimidinyl)-3- pyrrolidinecarboxamide

13-24 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(3-(trifluoromethyl)phenyl)-3- pyrrolidinecarboxamide

13-25 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(3,5 -dichlorophenyl)-3-pyrrolidinecarboxamide

13-26 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-(trifluoromethyl)-2-pyridinyl)-3- pyrrolidinecarboxamide

13-27 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(1-methyl-1H-pyrazol-4- yl)benzamide

13-28 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(4-methyl-1H-pyrazol-1- yl)benzamide

13-29 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(4-methyl-1H-pyrazol-1- yl)benzamide

13-30 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-7-methyl-1-(6-methyl-2-pyridinyl)-1H-indazole-5- carboxamide

15-2 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(2-quinolinyl)-1H-indazole-5-carboxamide

15-3 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-(1H-imidazol-yl)-2-pyridinyl)- 1H-indazole-5-carboxamide

15-4 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-phenyl-2-pyridinyl)-1H-indazole-5- carboxamide

15-5 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-(1H-pyrazol-1-yl)-2-pyridinyl)-1H-indazole-5- carboxamide

15-6 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-(1,1-difluoroethyl)-2-pyridinyl)-1H-indazole-5- carboxamide

15-7 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-(difluoromethoxy)-2-pyridinyl)-1H-indazole-5- carboxamide

15-8 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-(difluoromethyl)-2-pyridinyl)-1H-indazole-5- carboxamide

15-9 1-([2,2′-bipyridin]-6-yl)- N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1H- indazole-5-carboxamide

15-10 3-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3- azabicyclo[3.1.0]hexane-1-carboxamide

15-11 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-1H-pyrazole-3-carboxamide

15-12-2 (1S,4R,5S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-2-azabicyclo[3.1.0]hexane-4- carboxamide

15-12-1 (1S,4S,5S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(3,5-dichlorophenyl)-2-azabicyclo[3.1.0]hexane-4- carboxamide

15-14 N-((1S,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-1H-pyrazole-4- azepanecarboxamide

15-15 6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyano-2- pyridinyl)-1H-indazole-5-carboxamide

15-16 6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyano-2- pyridinyl)-1H-indazole-5-carboxamide

16-3 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1,3-thiazole-2-carboxamide

16-4 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-(3-cyanophenyl)-1,3-thiazole-2-carboxamide

16-5 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-(3-cyclopropylphenyl)-1,3-thiazole-4- carboxamide

20-1 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-7-(4-methyl-2-pyrimidinyl)-1H-indole-3-carboxamide

20-2 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-7-(6-methyl-2-pyridinyl)-1H-indole-3-carboxamide

20-3 2′,3-dichloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′- (cyanomethyl)[biphenyl]-4-carboxamide

20-4 3,3′-dichloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5′- (cyanomethyl)[biphenyl]-4-carboxamide

20-5 2′,3-dichloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5′- (cyanomethyl)[biphenyl]-4-carboxamide

20-6 3,4′-dichloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′- (cyanomethyl)[biphenyl]-4-carboxamide

20-7 3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-(2-cyano-2-propanyl)[biphenyl]-4-carboxamide

20-8 3-chloro-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3′-(2-cyanomethyl)-5′-fluoro[biphenyl]-4- carboxamide

20-9 3-chloro-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3′-(cyanomethyl)-4′-fluoro[biphenyl]-4- carboxamide

20-10 3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′- (cyanomethyl)-2′-fluoro[biphenyl]-4-carboxamide

20-11 3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5′- (cyanomethyl)-2′-fluoro[biphenyl]-4-carboxamide

20-12 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6- (2-(cyano-2-propanyl)-2-pyridinyl)benzamide

20-13 3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5′- (cyanomethyl)-2′-methyl[biphenyl]-4-carboxamide

20-14 3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′- (cyanomethyl)-4′-methyl[biphenyl]-4-carboxamide

20-15 3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′- (cyanomethyl)-5′-methyl[biphenyl]-4-carboxamide

20-16 3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′- (cyanomethyl)[biphenyl]- 4-carboxamide

20-17 3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′- (1-(cyanocyclobutyl)[biphenyl]-4-carboxamide

20-18 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(methoxymethyl)-2-pyridinyl)benzamide

20-19 3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4′- (cyanomethyl)[biphenyl]-4-carboxamide

20-20 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(5-(1-cyanocyclopropyl)-3-pyridinyl)benzamide

20-21 4-(6-(acetyl(methyl)amino)-2-pyridinyl)-2-chloro-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)benzamide

20-22 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(5- (cyanomethyl)-3-pyridinyl)benzamide

20-23 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4- (cyanomethyl)-2-pyridinyl)benzamide

20-24 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1-cyanocyclopropyl)-2- pyridinyl)-2- methylbenzamide

20-25 3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3′-(1-cyanocyclopropyl)[biphenyl]-4-carboxamide

20-26 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(2- (cyanomethyl)-3-pyridinyl)benzamide

20-27 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1-cyanocyclopropyl)-2-pyridinyl)-2- (trifluoromethyl)benzamide

20-28 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1-cyanocyclopropyl)-2-pyridinyl)-2- fluorobenzamide

20-29 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl- 1H-pyrazol-3-yl)-2-(trifluoromethyl)benzamide

20-30 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(imidazo[1,5-a]pyridin-6-yl)-2-(trifluoromethyl)benzamide

20-31 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-fluoro-4-(1-methyl-1H-pyrazol-3-yl)benzamide

20-32 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-fluoro-4-(imidazo[1,5-a]pyridin-6-yl)benzamide

20-33 2,6-dichloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl- 1H-pyrazol-3-yl)-benzamide

20-34 2,6-dichloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-imidazo[1,5- a]pyridin-6-yl)benzamide

20-35 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(5-cyano-2- pyrimidinyl)benzamide

20-36 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4-cyano-2- pyrimidinyl)benzamide

20-37 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-methyl-2- pyrazinyl)benzamide

20-38 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(5-methyl-2- pyrazinyl)benzamide

20-39 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4-cyano-2- pyridinyl)benzamide

20-40 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-methyl-2- pyridinyl)benzamide

20-41 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(2-methyl-4- pyrimidinyl)benzamide

20-42 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-methyl-3- pyradazinyl)benzamide

20-43 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(difluoromethyl)-2-pyridinyl)benzamide

20-44 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6- (cyanomethyl)-2-pyridinyl)benzamide

20-45 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(difluoromethoxy)-2-pyridinyl)benzamide

20-46 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1,1-(difluoroethyl)-2-pyridinyl)benzamide

20-47 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6- cyclopropyl-2-pyrazinyl)benzamide

20-48 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-cyano-2- pyridinyl)benzamide

20-49 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(1-cyanocyclopropyl)-2-pyridinyl)benzamide

20-50 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-(2,2,2-trifluoroethoxy)-2-pyridinyl)benzamide

20-51 2-chloro-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(imidazol[1,2-a]pyridin-6-yl)benzamide

20-52 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl- 1H-indazol-7-yl)benzamide

20-53 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(7-methylimidazo[1,2-a]pyridin-6-yl)benzamide

20-54 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(2-methylimidazo[1,2-a]pyridin-6-yl)benzamide

20-55 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(imidazo[1,2-a] pyridin-7-yl)benzamide

20-56 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(imidazo[1,5-a] pyridin-6-yl)benzamide

20-57 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl- 1H-pyrazol-3-yl)benzamide

20-58 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl- 1H-pyrazol-5-yl)benzamide

20-59 2-chloro-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(1-cyclopropyl- 1H-pyrazol-4-yl)benzamide

20-60 2-chloro-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(1-(cyanomethyl)- 1H-pyrazol-4-yl)benzamide

20-61 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-(methyl- 1H-imidazol-4-yl)benzamide

20-62 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-(methyl- 1H-pyrazol-4-yl)benzamide

20-63 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4-cyano-2-pyridinyl)-3-(2-methylpropoxy)benzamide

20-64 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(5-methyl-2- pyrazinyl)benzamide

20-65 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(6-methyl-2- pyridinyl)benzamide

20-66 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(4-methyl-2- pyrimidinyl)benzamide

20-67 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(6-(cyanomethyl)-2-pyridinyl)-3-(2- methylpropoxy)benzamide

20-68 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(1-methyl-1H- pyrazol-3-yl)benzamide

20-69 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(1-methyl-1H- pyrazol-5-yl)benzamide

20-70 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-methyl- 1H-imidazol-4-yl)-3-(2-methylpropoxy)benzamide

20-71 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(6-cyano-2-pyridinyl)-3-(2-methylpropoxy)benzamide

20-72 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(6-methyl-3- pyridazinyl)benzamide

20-73 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(2-methyl-4- pyrimidinyl)benzamide

20-74 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylbutoxy)-4-(1-methyl-1H- pyrazol-4-yl)benzamide

20-75 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(1-ethyl-1H-pyrazol-4-yl)-3-(2-methylpropoxy)benzamide

20-76 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-4-(1-cyclopropyl-1H- pyrazol-4-yl)-3-(2-methylpropoxy)benzamide

22-1 N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-methyl-2-pyridinyl)-7-(trifluoromethyl)-1H-indazole-5- carboxamide

23-7 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-(2,3-dichlorophenyl)-1-pyrrolidinecarboxamide

23-2 2-(3-bromo-2-methylphenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1- pyrrolidinecarboxamide

23-3 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-(2,3-dichlorophenyl)-1-azetidinecarboxamide

23-4 1-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-((-3-(2-propanyl)-2,3-dihydro-1H-inden-1- yl)methyl)urea

23-5 1-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(1-(2,3-dichlorophenyl)ethyl)urea

23-6 1-((7-chloro-1,2,3,4-tetrahydro-1-naphthalenyl)methyl)-3-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)urea

23-1 1-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(2-(2,5-dichlorophenyl)ethyl)urea

23-8 7-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxamide

23-9 8-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2- carboxamide

24-1 N′-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-N-(2-hydroxyethyl)-N- (tricyclo[3.3.1.1~3,7~]decan-1- ylmethyl)ethanediamide

25-3 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzamide

25-2 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4-(cyanomethyl)-1H-pyrazol-1-yl)benzamide

25-1 2-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(4- ethyl-1H-pyrazol-1-yl)benzamide

26-1-1 (3R)-1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-oxo- 3-pyrrolidinecarboxamide

26-1-1 (3S)-1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-5-oxo- 3-pyrrolidinecarboxamide

26-3 (3S)-1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)- 3-pyrrolidinecarboxamide

26-4 (3R)-1-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3- pyrrolidinecarboxamide

26-5 (2S)-5-bromo-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3-dihydro- 1H-indene-2-carboxamide

26-6 (2R)-5-bromo-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3-dihydro- 1H-indene-2-carboxamide

27-1 (3R)-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyclopropyl-2-pyrimidinyl)-3- pyrrolidinecarboxamide

27-2-1 (3R)-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(trifluoromethyl)-2-pyridinyl)-3- pyrrolidinecarboxamide

27-2-3 (3S)-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(trifluoromethyl)-2-pyridinyl)-3- pyrrolidinecarboxamide

28-1 (3S)-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5- dichlorophenyl)-3- pyrrolidinecarboxamide

28-2 (3S)-1-(5-chloro-2-cyanophenyl)-N- ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3- pyrrolidinecarboxamide

29-1 (3S)-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyano-4- (trifluoromethyl)-2-pyridinyl)-3-pyrrolidinecarboxamide

29-2 (3S)-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-cyano-4- methyl-2-pyridinyl)-3- pyrrolidinecarboxamide

29-3 (3S)-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-methyl-6- (trifluoromethyl)-2-pyridinyl)-3-pyrrolidinecarboxamide

29-4 (3S)-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(4-cyano-6- (trifluoromethyl)-2-pyridinyl)-3-pyrrolidinecarboxamide

29-5 (3S)-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3-cyano-6- (trifluoromethyl)-2-pyridinyl)-3-pyrrolidinecarboxamide

29-6 (3S)-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(trifluoromethyl)-2-pyrazinyl)-3- pyrrolidinecarboxamide

29-7 (3S)-1-(3-chloro-6-(trifluoromethyl)-2-pyridinyl)-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-pyrrolidinecarboxamide

30-1 (3S)-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3-methylphenyl)-3-pyrrolidinecarboxamide

30-2 (3S)-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3-methoxyphenyl)-3-pyrrolidinecarboxamide

30-3 7-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3-dihydro- 1-benzoxepine-4-carboxamide

30-4 (3S)-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(2,5-dichlorophenyl)-3-pyrrolidinecarboxamide

30-5 (3S)-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichloro-4-(trifluoromethoxy)phenyl-3- pyrrolidinecarboxamide

30-6 (3S)-1-(3-chloro-5-(trifluoromethyl)phenyl)-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-pyrrolidinecarboxamide

30-7 (3S)-1-(3-chloro-5-methylphenyl)-N- ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3- pyrrolidinecarboxamide

30-8 (3S)-1-(5-chloro-5-methylphenyl)-N- ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3- pyrrolidinecarboxamide

30-9 6-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2- pyridinecarboxamide

30-10 N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(2,5-dichlorophenyl)-2-pyridinecarboxamide

30-11 N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(3,5-dichlorophenyl)-2-pyridinecarboxamide

30-12 4-(3-chlorophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2- pyridinecarboxamide

30-13 (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichloro-4-methoxyphenyl)-3- pyrrolidinecarboxamide

30-14 (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichloro-4-fluorophenyl)-3- pyrrolidinecarboxamide

30-15 (3S)-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3-cyclopropylphenyl)-3- pyrrolidinecarboxamide

30-16 N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-4-(3,5-dichlorophenyl)-2-morpholinecarboxamide

30-17 (3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(2,3,5- trichlorophenyl)-3-pyrrolidinecarboxamide

31-1 N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-1H-pyrazole-carboxamide

31-2 3-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,5-dichlorophenyl)-1H-pyrazole-4-carboxamide

32-1 (3S)-1-(3-chloro-5- cyanophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3- pyrrolidinecarboxamide

32-2 (3S)-1-(2-chloro-5- cyanophenyl)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3- pyrrolidinecarboxamide

32-3 (3S)-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(2-oxo-1-(2-propanyl)-5- (trifluoromethyl)-1,2-dihydro-3-pyridinyl)-3-pyrrolidinecarboxamide

32-4 (3S)-N-((1R,2R,4S)-7- cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(3,4- dichlorophenyl)-3- pyrrolidinecarboxamide

32-5 (3S)-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(2,3-dichlorophenyl)-3-pyrrolidinecarboxamide

32-6 (3S)-1-(2-chloro-5-(trifluoromethyl)phenyl)-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-pyrrolidinecarboxamide

33-1-1 (1R,4R,5R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(3,5-dichlorophenyl)-2-azabicyclo[3.1.0]hexane-4- carboxamide

33-1-2 (1R,4R,5R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(3,5-dichlorophenyl)-2-azabicyclo[3.1.0]hexane-4- carboxamide

1-67-1 (3R)-6-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

12-31-1 (1S,3S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2,5-dichlorophenyl)cyclopentanecarboxamide

12-31-2 (1R,3R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2,5-dichlorophenyl)cyclopentanecarboxamide

12-30-2 (1S,3R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-3-(2,5-dichlorophenyl)cyclopentanecarboxamide

15-15-2 (5R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(1,1-difluoroethyl)-2-pyridinyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

15-16-2 (5R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1-(6-(difluoromethoxy)-2-pyridinyl)-4,5,6,7-tetrahydro-1H-indazole-5-carboxamide

15-16-3 (5S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(6-(1-cyanocyclopropyl)-2-pyridinyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

15-15-3 (5S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(6-(1,1-difluoroethyl)-2-pyridinyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

15-16-3 (5S)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(6- difluoroethyl)-2-pyridinyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

15-15-4 (5R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(6-(1,1-difluoroethyl)-2-pyridinyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

15-16-4 (5R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(6-(difluoromethoxy)-2-pyridinyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

15-17-4 (5R)-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2-(6-difluoromethyl)-2-pyridinyl)-4,5,6,7-tetrahydro-2H-indazole-5-carboxamide

17-1 7-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)- carboxamide

18-1 7-chloro-N-((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)-1,2,3,5-tetrahydro-4H-1,4-benzodiazepine-4- carboxamide

19-1 1-(6-acetamido-2-pyridinyl)-6-chloro-N- ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan-2-yl)- 1H-indazole-5-carboxamide

21-1-1 (5R)-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-methyl-2-pyridinyl)-4,5,6,7- tetrahydro-1H-indazole-5-carboxamide

21-1-2 (5S)-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(6-methyl-2-pyridinyl)-4,5,6,7- tetrahydro-1H-indazole-5-carboxamide

21-1-3 (5R)-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-(6-methyl-2-pyridinyl)-4,5,6,7- tetrahydro-2H-indazole-5-carboxamide

21-1-4 (5S)-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-(6-methyl-2-pyridinyl)-4,5,6,7- tetrahydro-1H-indazole-5-carboxamide

21-2-3 (5S)-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-(6-cyclopropyl-2-pyridinyl)-4,5,6,7- tetrahydro-2H-indazole-5-carboxamide

21-2-4 (5R)-N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-(6-cyclopropyl-2-pyridinyl)-4,5,6,7- tetrahydro-2H-indazole-5-carboxamide

20-77 N-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-3-(2-methylpropoxy)-4-(3-methyl-1H-pyrazol-1- yl)benzamide

Analytical Data for Experimental Examples:

Ex # Name MS data 1H NMR 1-1 N-((1R,2R,4S)-7-cyano- 364 1H NMR (500 MHz,DMSO-d6) δ 8.69 (d, J = 5.97 Hz, 1H), 8.57 7- (d, J = 1.69 Hz, 1H),7.96-8.00 (m, 1H), 7.93-7.96 (m, 1H), 7.64 azabicyclo[2.2.1]heptan- (t,J = 2.21 Hz, 2H), 6.44-6.46 (m, 2H), 4.29-4.36 (m, 1H), 4.262-yl)-2-(1H-pyrrol-1-yl)- (t, J = 4.54 Hz, 1H), 4.18 (t, J = 4.93 Hz,1H), 2.19-2.27 (m, 1H), 1,3-benzothiazole-6- 1.88-1.96 (m, 1H),1.78-1.88 (m, 1H), 1.65-1.74 (m, 2H), 1.57 carboxamide (dd, J = 4.67,12.72 Hz, 1H) 1-2 racemic-endo 2-methyl- 397.2 1H NMR (600 MHz, DMSO-d6)δ 8.44-8.59 (m, 1H), 7.67 (s, 2-propanyl 7-(7-cyano- 2H), 7.28 (br d, J= 8.56 Hz, 1H), 4.50-4.60 (m, 2H), 4.25-4.34 7- (m, 1H), 4.22 (t, J =4.55 Hz, 1H), 4.08-4.18 (m, 1H), 3.55-3.60 azabicyclo[2.2.1]heptan- (m,2H), 3.32 (s, 56H), 2.78-2.86 (m, 2H), 2.16-2.23 (m, 1H),2-yl)carbamoyl)-3,4- 1.77-1.87 (m, 2H), 1.62-1.73 (m, 2H), 1.50-1.60 (m,1H), 1.38- dihydro-2(1H)- 1.45 (m, 9H) isoquinolinecarboxylate 1-3racemic-endo 2-methyl- 397.2 1H NMR (600 MHz, DMSO-d6) δ 8.49 (d, J =Hz, 1H), 2-propanyl 6-(7-cyano- 7.64-7.70 (m, 2H), 7.27 (d, J = 7.86 Hz,1H), 4.55 (br s, 2H), 7- 4.24-4.30 (m, 1H), 4.23 (t., J = 4.59 Hz, 1H),4.16 (t, J = 4.67 Hz, azobicyclo[2.2.1]heptan- 1H), 3.53-3.60 (m, 2H),3.32 (s, 37H), 2.82 (br t, J = 5.76 Hz, 2-yl)carbamoyl)-3,4- 2H),2.17-2.23 (m, 1H), 1.78-1.88 (m, 2H), 1.62-1.72 (m, 2H), dihydro-2(1H)-1.55 (dd, J = 4.67, 12.69 Hz, 1H), 1.43 (s, 9H) isoquinolinecarboxylate1-4 N-((1R,2R,4S)-7-cyano- 411.2 1H NMR (600 MHz, DMSO-d6) δ 9.24 (s,1H), 8.53 (br d, 7- J = 6.00 Hz, 1H), 8.33 (d, J = 5.06 Hz, 1H), 8.09(dd, J = 6.42, azabicyclo[2.2.1]heptan- 12.73 Hz, 1H), 7.44 (dd, J =6.54, 10.98 Hz, 1H), 6.94 (d, J = 2-yl)-4-((4-cyclopropyl- 5.06 Hz, 1H),4.20-4.30 (m, 3H), 4.15 (t, J = 4.75 Hz, 1H), 2.16-2-pyrimidinyl)amino)- 2.24 (m, 2H), 2.02-2.08 (m, 1H), 1.87-1.95 (m,2H), 1.76-1.85 2,5-difluorobenzamide (m, 1H), 1.61-1.73 (m, 3H),1.40-1.50 (m, 1H), 0.99-1.09 (m, 4H) 1-5 N-((1R,2R,4S)-7-cyano- 411.2 1HNMR (600 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.64 (d, J = 6.15 7- Hz, 1H),8.27 (d, J = 5.14 Hz, 1H), 7.72 (t J = 7.69 Hz, 1H), 7.34azabicyclo[2.2.1]heptan- (br t, J = 7.24 Hz, 1H), 6.88 (d, J = 5.06 Hz,1H), 4.28 (br dd, 2-yl)-4-((4-cyclopropyl- J = 4.83, 11.13 Hz, 1H),4.21-4.26 (m, 1H), 4.16 (t, J = 4.79 Hz, 2-pyrimidinyl)amino)- 1H),3.16-3.23 (m, 1H), 2.16-2.24 (m, 1H), 1.99-2.04 (m, 1H),2,3-difluorobenzamide 1.86-1.94 (m, 1H), 1.78-1.85 (m, 1H), 1.60-1.74(m, 2H), 1.37- 1.51 (m, 1H), 0.98-1.06 (m, 4H) 1-6N-((1R,2R,4S)-7-cyano- 358.2 1H NMR (600 MHz, DMSO-d6) δ 13.52 (br s,1H), 8.73 (br d, 7- J = 5.99 Hz, 1H), 8.11 (d, J = 8.81 Hz, 1H), 8.06(s, 1H), 7.97 (br azabicyclo[2.2.1]heptan- d, J = 7.24 Hz, 2H), 7.65 (d,J = 8.49 Hz, 1H), 7.50 (t, J = 7.71 Hz, 2-yl)-3-phenyl-1H- 2H), 7.39 (t,J = 7.60 Hz, 1H), 4.31 (br dd, J = 4.79, 11.02 Hz, 1H),indazole-6-carboxamide 4.24 (t, J = 4.52 Hz, 1H), 4.14 (t, J = 4.90 Hz,1H), 2.16-2.23 (m, 1H), 1.84-1.91 (m, 1H), 1.75-1.84 (m, 1H), 1.62-1.72(m, 2H), 1.57 (dd, J = 4.59, 12.77 Hz, 1H) 1-7 2-methyl-2-propanyl (4-371.2 1H NMR (600 MHz, DMSO-d6,) δ 8.61 (s, 1H), 8.39 (d, J = 5.99(((1R,2R,4S)-7-cyano-7- Hz, 1H), 7.62 (s, 1H), 7.59 (d, J = 8.53 Hz,1H), 7.47 (d, J = 8.41 azabicyclo[2.2.1]heptan- Hz, 1H), 4.19-4.24 (m,1H), 4.17 (t, J = 4.55 Hz, 1H), 4.11 (t, 2-yl)carbamoyl)-2- J = 4.79 Hz,1H), 2.21 (s, 3H), 2.09-2.18 (m, 1H), 1.71-1.84 (m,methylphenyl)carbamate 2H), 1.57-1.68 (m, 2H), 1.47-1.55 (m, 1H), 1.43(s, 9H) 1-8 N-((1R,2R,4S)-7-cyano- 367.2 1H NMR (600 MHz, DMSO-d6) δ8.39 (d, J = 5.99 Hz, 1H), 8.08 7- (d, J = 8.49 Hz, 1H), 7.71 (s, 1H),7.66 (dd, J = 1.83, 8.52 Hz, 1H), azabicyclo[2.2.1]heptan- 4.21-4.28 (m,3H), 4.17 (t, J = 4.52 Hz, 1H), 4.11 (t, J = 4.75 Hz, 2-yl)-1-(2,2- 1H),3.10-3.15 (m, 2H), 2.10-2.21 (m, 1H), 1.70-1.87 (m, 2H),dimethylpropanoyl)-2,3- 1.58-1.69 (m, 2H), 1.52 (dd, J = 4.71, 12.65 Hz,1H), 1.20-1.28 dihydro-1H-indole-5- (m, 9H) carboxamide 1-9N-((1R,2R,4S)-7-cyano- 325 1H NMR (600 MHz, DMSO-d6) δ 9.28 (d, J = 1.87Hz, 1H), 8.67 7- (d, J = 5.92 Hz, 1H), 8.38 (d, J = 1.87 Hz, 1H),8.12-8.18 (m, azabicyclo[2.2.1]heptan- J = 8.49 Hz, 2H), 7.97-8.02 (m, J= 8.56 Hz, 2H), 4.32-4.39 (m, 2-yl)-4-(1,3-thiazol-4- 1H), 4.30 (t, J =4.55 Hz, 1H), 4.22 (t, J = 4.87 Hz, 1H), 2.23-2.29 yl)benzamide (m, 1H),1.82-1.97 (m, 2H), 1.69-1.78 (m, 2H), 1.63 (dd, J = 4.67, 12.69 Hz, 1H)1-10 4-benzamido-N- 361.2 1H NMR (600 MHz, DMSO-d6) δ 10.42 (s, 1H),8.45 (d, J = 6.07 ((1R,2R,4S)-7-cyano-7- Hz, 1H), 7.90-7.97 (m, 4H),7.57 (t, J = 7.59 Hz, 2H), 7.51 (t, azabicyclo[2.2.1]heptan- J = 7.35Hz, 3H), 4.22-4.29 (m, 1H), 4.19 (t, J = 4.52 Hz, 1H), 4.122-yl)benzamide (t, J = 4.87 Hz, 1H), 2.12-2.20 (m, 1H), 1.73-1.87 (m,2H), 1.60- 1.69 (m, 2H), 1.53 (dd, J = 4.67, 12.69 Hz, 1H) 1-11N-(4-(((1R,2R,4S)-7- 362.2 1H NMR (600 MHz, DMSO-d6) δ 10.85 (s, 1H),8.76 (s, 1H), cyano-7- 8.49 (d, J = 5.99 Hz, 1H), 8.18 (d, J = 7.92 Hz,1H), 8.09 (dt, azabicyclo[2.2.1]heptan- J = 1.67, 7.69 Hz, 1H),8.01-8.07 (m, 2H), 7.89 (d, J = 8.72 Hz, 2-yl)carbamoyl)phenyl)- 2H),7.70 (ddd, J = 1.21, 4.75, 7.51 Hz, 1H), 4.26-4.33 (m, 1H),2-pyridinecarboxamide 4.23 (t, J = 4.59 Hz, 1H), 4.16 (t, J = 4.87 Hz,1H), 2.17-2.24 (m, 1H), 1.77-1.92 (m, 2H), 1.64-1.73 (m, 2H), 1.56 (dd,J = 4.71, 12.73 Hz, 1H) 1-12 N-((1R,2R,4S)-7-cyano- 342.2 1H NMR (600MHz, DMSO-d6) δ 8.67 (d, J = 6.07 Hz, 1H), 7.92 7- (d, J = 8.49 Hz, 2H),7.67 (d, J = 8.49 Hz, 2H), 7.59 (td, J = 2.82, azabicyclo[2.2.1]heptan-3.93 Hz, 2H), 7.43-7.47 (m, 3H), 4.27-4.33 (m, 1H), 4.24 (t, 2-yl)-4- J= 4.52 Hz, 1H), 4.17 (t, J = 4.87 Hz, 1H), 2.18-2.24 (m, 1H),(phenylethynyl)benzamide 1.78-1.91 (m, 2H), 1.64-1.73 (m, 2H), 1.57 (dd,J = 4.67, 12.77 Hz, 1H) 1-13 6-(1H-benzimidazol-1- 359.2 1H NMR (600MHz, DMSO-d6) δ 9.08 (s, 2H), 8.83 (d, J = 5.99 yl)-N-((1R,2R,4S)-7- Hz,1H), 8.46 (dd, J = 2.41, 8.56 Hz, 1H), 8.40 (d, J = 7.86 Hz, cyano-7-1H), 8.11 (d, J = 8.56 Hz, 1H), 7.80 (d, J = 7.94 Hz, 1H), 7.39-7.45azabicyclo[2.2.1]heptan- (m, 1H), 7.34-7.39 (m, 1H), 4.31-4.38 (m, 1H),4.28 (t, J = 4.44 2-yl)-3- Hz, 1H), 4.19 (t, J = 4.90 Hz, 1H), 2.22-2.29(m, 1H), 1.90-1.97 pyridinecarboxamide (m, 1H), 1.80-1.89 (m, 1H),1.66-1.75 (m, 2H), 1.56 (dd, J = 4.67, 12.77 Hz, 1H) 1-144-((5-chloro-2- 369 1H NMR (600 MHz, DMSO-d6) δ 8.57 (d, J = 5.99 Hz,1H), 8.22 pyridinyl)oxy)-N- (d, J = 2.72 Hz, 1H), 8.00 (d, J = 9.01 Hz,1H), 7.91 (d, J = 8.04 Hz, ((1R,2R,4S)-7-cyano-7- 2H), 7.22-7.27 (m,2H), 7.17 (d, J = 8.80 Hz, 1H), 4.26-4.32 (m, azabicyclo[2.2.1]heptan-1H), 4.24 (t, J = 4.44 Hz, 1H), 4.16 (t, J = 4.87 Hz, 1H), 2.17-2.252-yl)benzamide (m, 1H), 1.77-1.91 (m, 2H), 1.63-1.72 (m, 2H), 1.55 (dd,J = 4.71, 12.73 Hz, 1H) 1-15 N-((1R,2R,4S)-7-cyano- 354.2 1H NMR (600MHz, DMSO-d6) δ 8.70 (d, J = 5.99 Hz, 1H), 7.86 7- (dd, J = 1.71, 11.13Hz, 1H), 7.79 (dd, J = 1.63, 8.25 Hz, 1H), 7.58 azabicyclo[2.2.1]heptan-(t, J = 7.98 Hz, 1H), 6.06 (s, 1H), 4.22-4.28 (m, 1H), 4.20 (t,2-yl)-4-(3,5-dimethyl- J = 4.36 Hz, 1H), 4.13 (t, J = 4.87 Hz, 1H),2.14-2.20 (m, 1H), 2.13 1H-pyrazol-1-yl)-3- (s, 3H), 2.09 (s, 3H),1.74-1.88 (m, 2H), 1.58-1.68 (m, 2H), 1.51 fluorobenzamide (dd, J =4.67, 12.77 Hz, 1H) 1-16 2-chloro-N-((1R,2R,4S)- 395 1H NMR (600 MHz,DMSO-d6) δ 8.76 (br d, J = 5.76 Hz, 1H), 7-cyano-7- 7.51 (d, J = 8.49Hz, 1H), 7.29 (d, J = 2.18 Hz, 1H), 7.25 (d, J = 8.56azabicyclo[2.2.1]heptan- Hz, 1H), 4.25-4.31 (m, 2H), 4.18 (t, J = 4.94Hz, 1H), 3.82 (t, 2-yl)-4-(1,1-dioxido-1,2- J = 6.54 Hz, 2H), 3.61 (t, J= 7.36 Hz, 2H), 2.18-2.29 (m, 1H), thiazolidin-2- 1.97-2.06 (m, 1H),1.79-1.89 (m, 1H), 1.70-1.79 (m, 1H), 1.58- yl)benzamide 1.67 (m, 1H),1.41 (dd, J = 4.01, 12.88 Hz, 1H) 1-17 2-methyl-2-propanyl (3- 391.2 1HNMR (600 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.70 (br d,chloro-4-(((1R,2R,4S)-7- J = 5.68 Hz, 1H), 7.71 (s, 1H), 7.39-7.48 (m,2H), 4.26-4.32 (m, cyano-7- 2H), 4.20 (t, J = 4.94 Hz, 1H), 2.21-2.29(m, 1H), 2.03 (ddd, azabicyclo[2.2.1]heptan- J = 4.24, 8.99, 12.92 Hz,1H), 1.80-1.91 (m, 1H), 1.70-1.79 (m, 2- 1H), 1.62-1.68 (m, 1H), 1.54(s, 8H), 1.44 (dd, J = 4.05, 12.85 Hz, yl)carbamoyl)phenyl)carbamate 1H)1-18 N-((1R,2R,4S)-7-cyano- 355.2 1H NMR (600 MHz, DMSO-d6) δ 9.38 (s,1H), 8.53 (d, J = 5.99 7- Hz, 1H), 7.76 (s, 1H), 7.71 (dd, J = 1.87,8.25 Hz, 1H), 7.62 (br d, azabicyclo[2.2.1]heptan- J = 8.33 Hz, 1H),4.25-4.36 (m, 2H), 4.22 (t, J = 4.79 Hz, 1H), 2-yl)-3-methyl-4-(3-2.29-2.35 (m, 5H), 2.23-2.29 (m, 1H), 2.14 (td, J = 6.86, 13.60methylbutanamido)benzamide Hz, 1H), 1.83-1.95 (m, 2H), 1.68-1.79 (m,2H), 1.61 (dd, J = 4.67, 12.69 Hz, 1H), 1.02 (d, J = 6.62 Hz, 6H) 1-19N-(1R,2R,4S)-7-cyano- 322.2 1H NMR (600 MHz, DMSO-d6) δ 8.64 (d, J =5.92 Hz, 1H), 8.43 7- (s, 1H), 8.03 (d, J = 8.20 Hz, 2H), 7.95 (d, J =8.22 Hz, 2H), 7.67 azabicyclo[2.2.1]heptan- (s, 1H), 4.33-4.38 (m, 1H),4.29 (t, J = 4.52 Hz, 1H), 4.22 (t, 2-yl)-4-(4-methyl-1H- J = 4.94 Hz,1H), 2.21-2.30 (m, 1H), 2.17 (s, 3H), 1.84-1.96 (m,pyrazol-1-yl)benzamide 2H), 1.70-1.78 (m, 2H), 1.62 (dd, J = 4.75, 12.77Hz, 1H) 1-20 4-(1H-benzotriazol-1- 359.2 1H NMR (600 MHz, DMSO-d6) δ8.76 (d, J = 5.99 Hz, 1H), 8.19 yl)-N-((1R,2R,4S)-7- (d, J = 8.41 Hz,1H), 8.14 (d, J = 7.98 Hz, 2H), 7.99-8.04 (m, 2H), cyano-7- 7.97 (d, J =8.41 Hz, 1H), 7.68 (ddd, J = 0.93, 7.06, 8.27 Hz, 1H),azabicycio[2.2.1]heptan- 7.52 (ddd, J = 0.82, 7.10, 8.19 Hz, 1H),4.27-4.34 (m, 1H), 4.25 2-yl)benzamide (t, J = 4.32 Hz, 1H), 4.15 (t, J= 4.87 Hz, 1H), 4.05 (br d, J = 5.37 Hz, 1H), 3.11-3.15 (m, 2H),2.17-2.24 (m, 1H), 1.84-1.91 (m, 1H), 1.76-1.84 (m, 1H), 1.63-1.71 (m,2H), 1.56 (dd, J = 4.71, 12.73 Hz, 1H) 1-21 N-((1R,2R,4S)-7-cyano- 319.21H NMR (600 MHz, DMSO-d6) δ 8.72-8.78 (m, 3H), 8.27 (t, 7- J = 1.52 Hz,1H), 7.99-8.06 (m, 2H), 7.80-7.85 (m, 2H), 7.69-7.74azabicyclo[2.2.1]heptan- (m, 1H), 4.36-4.43 (m, 1H), 4.31-4.36 (m, 1H),4.24 (t, J = 4.90 2-yl)-3-(4- Hz, 1H), 2.25-2.36 (m, 1H), 1.93-1.99 (m,1H), 1.86-1.93 (m, pyridinyl)benzamide 1H), 1.71-1.78 (m, 2H), 1.63 (dd,J = 4.67, 12.69 Hz, 1H) 1-22 N-((1R,2R,4S)-7-cyano- 313.2 1H NMR (600MHz, DMSO-d6) δ 8.64 (d, J = 2.49 Hz, 1H), 8.54 7- (d, J = 5.99 Hz, 1H),8.12 (dd, J = 2.49, 8.72 Hz, 1H), 6.90 (d, azabicyclo[2.2.1]heptan- J =8.72 Hz, 1H), 4.24-4.30 (m, 1H), 4.22 (t, J = 4.40 Hz, 1H), 2-yl)-6-4.11-4.17 (m, 3H), 2.17-2.23 (m, 1H), 1.77-1.90 (m, 2H), 1.63-(cyclopropylmethoxy)-3- 1.70 (m, 2H), 1.51 (dd, J = 4.67, 12.69 Hz, 1H),1.21-1.28 (m, pyridinecarboxamide 1H), 0.51-0.60 (m, 2H), 0.32-0.37 (m,2H) 1-23 4-(3-chloro-2-pyridinyl)- 353.2 1H NMR (600 MHz, DMSO-d6) δ8.63-8.66 (m, 1H), 8.61 (s, N-((1R,2R,4S)-7-cyano- 1H), 8.03 (dd, J =1.40, 8.10 Hz, 1H), 7.89-7.94 (m, 2H), 7.71- 7- 7.75 (m, 2H), 7.44 (dd,J = 4.59, 8.10 Hz, 1H), 4.24-4.31 (m, 1H), azabicyclo[2.2.1]heptan- 4.21(t, J = 4.48 Hz, 1H), 4.12 (t, J = 4.90 Hz, 1H), 2.14-2.20 (m,2-yl)benzamide 1H), 1.82-1.88 (m, 1H), 1.73-1.82 (m, 1H), 1.60-1.68 (m,2H), 1.53 (dd, J = 4.67, 12.69 Hz, 1H) 1-24 N-((1R,2R,4S)-7-cyano- 319.21H NMR (600 MHz, DMSO-d6) δ 8.93 (d, J = 1.71 Hz, 1H), 8.62 7- (d, J =6.07 Hz, 1H), 8.58 (dd, J = 1.52, 4.71 Hz, 1H), 8.11 (d,azabicyclo[2.2.1]heptan- J = 7.89 Hz, 1H), 7.93-7.98 (m, J = 8.49 Hz,2H), 7.81-7.85 (m, 2-yl)-4-(3- J = 8.49 Hz, 2H), 7.48 (ddd, J = 0.78,4.75, 7.94 Hz, 1H), 4.24-4.32 pyridinyl)benzamide (m, 1H), 4.22 (t, J =4.59 Hz, 1H), 4.13 (t, J = 4.94 Hz, 1H), 2.15- 2.21 (m, 1H), 1.75-1.88(m, 2H), 1.61-1.70 (m, 2H), 1.55 (dd, J = 4.71, 12.73 Hz, 1H) 1-25N-((1R,2R,4S)-7-cyano- 322.2 1H NMR (500 MHz, DMSO-d6) Shift 8.57 (d, J= 6.10 Hz, 1H), 7- 8.47 (d, J = 2.47 Hz, 1H), 7.95-8.01 (m, 2H),7.88-7.92 (m, 2H), azobicyclo[2.2.1]heptan- 4.31 (br dd, J = 4.87, 11.09Hz, 1H), 4.23-4.26 (m, 1H), 4.17 (t, 2-yl)-4-(3-methyl-1H- J = 4.87 Hz,1H), 2.29 (s, 3H), 2.17-2.25 (m, 1H), 1.78-1.92 (m,pyrazol-1-yl)benzamide 2H), 1.69 (ddd, J = 3.70, 8.73, 12.49 Hz, 2H),1.57 (dd, J = 4.67, 12.72 Hz, 1H) 1-26 N-((1R,2R,4S)-7-cyano- 376.2 1HNMR (600 MHz, DMSO-d6) Shift 9.24 (s, 1H), 8.60 (d, 7- J = 5.99 Hz, 1H),8.20 (s, 1H), 7.92-8.00 (m, 4H), 4.20-4.28 (m, azabicyclo[2.2.1]heptan-1H), 4.18 (t, J = 4.48 Hz, 1H), 4.10 (t, J = 4.90 Hz, 1H), 2.10-2.192-yl)-4-(4- (m, 1H), 1.71-1.85 (m, 2H), 1.57-1.66 (m, 2H), 1.50 (dd, J =4.67, (trifluoromethyl)-1H- 12.77 Hz, 1H) pyrazol-1-yl)benzamide 1-27N-((1R,2R,4S)-7-cyano- 373.2 1H NMR (600 MHz, DMSO-d6) Shift 8.68 (dd, J= 1.48, 4.59 7- Hz, 1H), 8.61 (d, J = 5.99 Hz, 1H), 8.43 (d, J = 8.80Hz, 2H), 8.37 azabicyclo[2.2.1]heptan- (dd, J = 1.48, 7.94 Hz, 1H), 8.07(d, J = 8.80 Hz, 1H), 7.98-8.04 2-yl)-4-(3-methyl-1H- (m, 2H), 7.28-7.42(m, 2H), 7.03 (dd, J = 8.76, 15.92 Hz, 1H), pyrazolo[3,4-b]pyridin-4.26-4.33 (m, 1H), 4.24 (t, J = 4.55 Hz, 1H), 4.15 (t, J = 4.90 Hz,1-yl)benzamide 1H), 3.79 (d, J = 6.70 Hz, 1H), 2.60-2.63 (m, 3H),2.15-2.25 (m, 1H), 1.83-1.96 (m, 1H), 1.75-1.83 (m, 1H)), 1.63-1.74 (m,2H), 1.57 (dd, J = 4.71, 12.81 Hz, 1H) 1-28 2-chloro-N-((1R,2R,4S)- 3561H NMR (600 MHz, DMSO-d6) Shift 8.77 (br d, J = 5.76 Hz, 7-cyano-7- 1H),8.37 (s, 1H), 7.91 (d, J = 2.10 Hz, 1H), 7.79 (dd, J = 2.18,azabicyclo[2.2.1]heptan- 8.41 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J = 8.41Hz, 1H), 4.17-4.28 2-yl)-4-(4-methyl-1H- (m, 2H), 4.11 (t, J = 4.90 Hz,1H), 2.11-2.23 (m, 1H), 2.06 (s, pyrazol-1-yl)benzamide 3H), 1.89-2.02(m, 1H), 1.72-1.85 (m, 1H), 1.64-1.72 (m, 1H), 1.46-1.60 (m, 1H), 1.35(dd, J = 3.97, 12.77 Hz, 1H) 1-29 N-((1R,2R,4S)-7-cyano- 340 1H NMR (600MHz, DMSO-d6) Shift 8.71 (d, J = 6.15 Hz, 1H), 7- 8.46 (s, 1H),7.68-7.83 (m, 4H), 4.28-4.37 (m, 2H), 4.21 (t, azabicyclo[2.2.1]heptan-J = 4.90 Hz, 1H), 2.20-2.31 (m, 1H), 2.16 (s, 3H), 1.93-2.05 (m,2-yl)-2-fluoro-4-(4- 1H), 1.82-1.92 (m, 1H), 1.66-1.80 (m, 2H), 1.50(dd, J = 4.52, methyl-1H-imidazol-1- 12.77 Hz, 1H) yl)benzamide 1-30N-((1R,2R,4S)-7-cyano- 336.2 1H NMR (600 MHz, DMSO-d6) Shift 8.65 (d, J= 5.84 Hz, 1H), 7- 8.37 (s, 1H), 7.97 (s, 1H), 7.77 (d, J = 1.71 Hz,1H), 7.74 (dd, azabicyclo[2.2.1]heptan- J = 2.10, 8.72 Hz, 2H), 7.52 (d,J = 8.33 Hz, 1H), 4.33-4.38 (m, 2-yl)-2-methyl-4-(4- 1H), 4.28-4.33 (m,1H), 4.27-4.39 (m, 1H), 4.21 (t, J = 4.87 Hz, methyl-1H-pyrazol-1- 1H),2.65 (s, 3H), 2.44-2.48 (m, 3H), 2.27 (br s, 1H), 1.96-2.02 yl)benzamide(m, 2H), 1.87 (dt, J = 4.01, 7.57 Hz, 1H), 1.74-1.81 (m, 1H), 1.65- 1.74(m, 1H), 1.49 (dd, J = 4.44, 12.69 Hz, 1H), 0.12-0.15 (m, 1H) 1-31N-((1R,2R,4S)7-cyano- 340 1H NMR (600 MHz, DMSO-d6) Shift 8.65 (d, J =5.76 Hz, 1H), 7- 8.04 (s, 1H), 7.86-7.93 (m, 2H), 7.81 (dd, J = 1.71,8.49 Hz, 1H), azabicyclo[2.2.1]heptan- 7.64 (s, 1H), 4.18-4.30 (m, 2H),4.14 (t, J = 4.83 Hz, 1H), 2.12- 2-yl)-3-fluoro-4-(4- 2.21 (m, 1H), 2.08(s, 3H), 1.72-1.87 (m, 2H), 1.59-1.71 (m, methyl-1H-pyrazol-1- 2H), 1.52(dd. J = 4.63, 12.73 Hz, 1H) yl)benzamide 1-32 racemic-endo N-(7- 337.2¹H NMR (500 MHz, DMSO-d6) δ 9.11 (d, J = 6.49 Hz, 1H), 8.94 cyano-7- (d,J = 1.82 Hz, 1H, 8.28 (dd, J = 2.34, 8.17 Hz, 1H), 8.09 (d,azabicyclo[2.2.1]heptan- J = 8.17 Hz, 1H), 7.87 (t, J = 6.52 Hz, 2H),7.39 (t, J = 8.21 Hz, 2-yl)-5-(4-fluorophenyl)- 2H), 4.31-4.38 (m, 1H),4.25 (t, J = 4.61 Hz, 1H), 4.17 (t, J = 4.61 2-pyridinecarboxamide Hz,1H), 2.14-2.23 (m, 1H), 1.75-1.88 (m, 4H), 1.63-1.73 (m, 1H) 1-33racemic-endo 6-(4- 353.2 ¹H NMR (500 MHz, DMSO-d₆) δ 9.09 (d, J = 2.21Hz, 1H), 8.79 chlorophenyl)-N-(7- (d, J = 6.10 Hz, 1H), 8.30 (dd, J =2.21, 8.30 Hz, 1H), 8.12-8.21 cyano-7- (m, 3H), 7.59 (d, J = 8.56 Hz,2H), 4.24-4.36 (m, 2H), 4.18 (t, azabicyclo[2.2.1]heptan- J = 4.87 Hz,1H), 2.20-2.28 (m, 1H), 1.78-1.94 (m, 2H), 1.64-1.73 2-yl)-3- (m, 2H),1.55 (dd, J = 4.67, 12.72 Hz, 1H) pyridinecarboxamide 1-346-(4-chlorophenyl)-N- 353.2 ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (s, 1H),8.79 (br d, ((1R,2R,4S)-7-cyano-7- J = 5.97 Hz, 1H), 8.31 (dd, J = 1.88,8.24 Hz, 1H), 8.17-8.21 (m, azabicyclo[2.2.1]heptan- J = 8.43 Hz, 2H),8.13 (d, J = 8.30 Hz, 1H), 7.57-7.61 (m, J = 8.56 2-yl)-3- Hz, 2H), 4.33(br dd, J = 5.32, 10.90 Hz, 1H), 4.26 (t, J = 4.15 Hz,pyridinecarboxamide 1H), 4.18 (t, J = 4.74 Hz, 1H), 2.20-2.28 (m, 1H),1.87-1.94 (m, 1H), 1.79-1.87 (m, 1H), 1.65-1.74 (m, 2H), 1.55 (dd, J =4.67, 12.72 Hz, 1H) 1-35 racemic-endo N-(7- 349 ¹H NMR (500 MHz,DMSO-d₆) δ 10.05 (s, 1H), 8.89 (s, 2H), cyano-7- 8.49 (d, J = 6.10 Hz,1H), 7.54-7.62 (m, 2H), 7.19 (t, J = 7.79 Hz, azabicyclo[2.2.1]heptan-1H), 6.83 (d, J = 7.48 Hz, 1H), 4.25-4.33 (m, 1H), 4.25-4.32 (m,2-yl)-2-(3- 1H), 4.15-4.32 (m, 1H), 2.16-2.34 (m, 4H), 1.76-1.99 (m,2H), methylanilino)-5- 1.62-1.72 (m, 2H), 1.50 (dd, J = 4.67, 12.72 Hz,1H) pyrimidinecarboxamide 1-36 N-((1R,2R,4S)-7-cyano- 417.2 ¹H NMR (500MHz, DMSO-d₆) δ 8.74 (d, J = 6.36 Hz, 1H), 8.54 7- (d, J = 0.78 Hz, 1H),8.37 (d, J = 11.68 Hz, 1H), 8.16 (d, J = 6.88 azabicyclo[2.2.1]heptan-Hz, 1H), 7.87 (t, J = 7.75 Hz, 1H), 7.76 (dd, J = 0.78, 8.17 Hz,2yl)-1-(6-cyclopropyl- 1H), 7.30 (dd, J = 0.71, 7.59 Hz, 1H), 4.25-4.36(m, 2H), 4.17 (t, 2-pyridinyl)-6-fluoro- J = 4.93 Hz, 1H), 2.20-2.30 (m,2H), 1.92-2.03 (m, 1H), 1.78-1.88 1H-indazole-5- (m, 1H), 1.60-1.78 (m,2H), 1.45 (dd, J = 4.41, 12.72 Hz, 1H), carboxamide 1.06-1.16 (m, 4H)1-37 N-((1R,2R,4S)-7-cyano- 398.2 ¹H NMR (600 MHz, DMSO-d₆) δ 8.80 (d, J= 8.87 Hz, 1H), 8.73 7- (d, J = 5.92 Hz, 1H), 8.68 (s, 1H), 8.44-8.50(m, 1H), 8.16 (s, azobicyclo[2.2.1]heptan- 1H), 8.09 (dd, J = 1.56, 8.88Hz, 1H), 7.65-7.72 (m, 1H), 4.35 (br 2-yl)-1-(4-cyano-6- dd, J = 4.90,11.05 Hz, 1H), 4.28 (t, J = 4.48 Hz, 1H), 4.19 (t,methyl-2-pyridinyl)-1H- J = 4.87 Hz, 1H), 2.67-2.72 (m, 3H), 2.21-2.27(m, 1H), 1.90-1.97 indazole-5-carboxamide (m, 1H), 1.81-1.87 (m, 1H),1.67-1.75 (m, 2H), 1.59 (dd, J = 4.63, 12.73 Hz, 1H) 1-38N-((1R,2R,4S)-7-cyano, 373.2 ¹H NMR (600 MHz, DMSO-d₆) δ 8.91 (d, J =2.02 Hz, 1H), 8.72 7- (d, J = 6.53 Hz, 1H), 8.69 (s, 1H), 8.59 (d, J =2.18 Hz, 1H), 8.46 azabicyclo[2.2.1]heptan- (d, J = 3.81 Hz, 1H), 8.41(d, J = 5.06 Hz, 1H), 7.22 (d, J = 5.53 Hz, 2-yl)-1-(4-methyl-2- 1H),6.89 (d, J = 3.81 Hz, 1H), 4.32-4.41 (m, 1H), 4.28 (t, J = 4.44pyridinyl)-1H- Hz, 1H), 4.19 (t, J = 4.90 Hz, 1H), 2.46-2.49 (m, 3H),2.22-2.29 pyrrolo[2,3-b]pyridine- (m, 1H), 1.91-1.98 (m, 1H), 1.80-1.88(m, 1H), 1.66-1.76 (m, 5-carboxamide 2H), 1.58 (dd, J = 4.71, 12.73 Hz,1H) 1-39 N-((1R,2R,4S)-7-cyano- 379.2 ¹H NMR (600 MHz, DMSO-d₆) δ 8.75(d, J = 5.99 Hz, 1H), 8.64 7- (s, 1H), 8.54 (d, J = 8.80 Hz, 1H), 8.47(d, J = 0.78 Hz, 1H), 8.12 azabicyclo[2.2.1]heptan- (dd, J = 1.63, 8.80Hz, 1H), 7.09 (d, J = 1.09 Hz, 1H), 4.31-4.37 2yl-1-(4-methyl-1,3- (m,1H), 4.28 (t, J = 4.48 Hz, 1H), 4.19 (t, J = 4.87 Hz, 1H), 2.44thiazol-2-yl)-1H- (d, J = 1.01 Hz, 3H), 2.20-2.28 (m, 1H), 1.90-1.96 (m,1H), 1.79- indazole-5-carboxamide 1.88 (m, 1H), 1.69-1.73 (m, 2H), 1.59(dd, J = 4.75, 12.69 Hz, 1H) 1-40 Mixture of two 377.2 ¹H NMR (500 MHz,DMSO-d₆) δ 8.30 (s, 1H), 8.19-8.24 (m, diastereomers: (S)-N-(7- 1H),7.79 (t, J = 7.85 Hz, 1H), 7.59-7.62 (m, 1H), 7.11-7.14 (m, cyano-7-1H), 4.09-4.15 (m, 3H), 2.72-2.85 (m, 2H), 2.60-2.68 (m, 2H)azabicyclo[2.2.1]heptan- 2.52-2.56 (m, 1H), 2.48 (s, 3H), 2.13-2.23 (m,1H), 2.01-2.06 2-yl)-1-(6-methyl-2- (m, 1H), 1.73-1.87 (m, 3H),1.65-1.69 (m, 1H), 1.58-1.62 (m, pyridinyl)-4,5,6,7- 1H), 1.28 (m, 1H)tetrahydro-1H-indazole- 5-carboxamide and (R)-N-(7-cyano-7-azabicyclo[2.2.1]heptan- 2-yl)-1-(6-methyl-2- pyridinyl)-4,5,6,7-tetrahydro-1H-indazole- 5-carboxamide 1-41 N-((1R,2R,4S)-7-cyano- 373 ¹HNMR (600 MHz, DMSO-d₆) δ 9.28 (d, J = 0.86 Hz, 1H), 8.75 7- (d, J = 5.06Hz, 1H), 8.62 (d, J = 6.23 Hz, 1H), 8.42 (d, J = 3.58 Hz,azobicyclo[2.2.1]heptan- 1H), 7.72 (d, J = 1.01 Hz, 2H), 7.29 (d, J =5.06 Hz, 1H), 6.85 (dd, 2-yl)-3-(4-methyl-2- J = 0.70, 3.66 Hz, 1H),4.36 (br dd, J = 4.87, 11.09 Hz, 1H), 4.28 pyrimidinyl)-1H-indole- (t, J= 4.63 Hz, 1H), 4.17 (t, J = 4.90 Hz, 1H), 2.58-2.60 (m, 3H),6-carboxamide 2.35-2.39 (m, 1H), 2.18-2.26 (m, 1H), 1.89-1.99 (m, 1H),1.78- 1.86 (m, 1H), 1.66-1.76 (m, 2H), 1.61 (dd, J = 4.71, 12.73 Hz, 1H)1-42 N-((1R,2R,4S)-7-cyano- 403 ¹H NMR (600 MHz, DMSO-d₆) δ 8.73 (d, J =4.98 Hz, 1H), 8.55 7- (s, 1H), 8.38 (d, J = 6.23 Hz, 1H), 8.22 (d, J =3.66 Hz, 1H), 7.89 azabicyclo[2.2.1]heptan- (s, 1H), 7.26 (d, J = 5.06Hz, 1H), 6.78 (d, J = 3.27 Hz, 1H), 4.25- 2-yl)-6-methoxy-1-(4- 4.36 (m,2H), 4.16 (t, J = 4.87 Hz, 1H), 3.96 (s, 3H), 2.58-2.64methyl-2-pyrimidinyl)- (m, 3H), 2.21-2.28 (m, 1H), 1.94-2.01 (m, 1H),1.82 (dt, J = 3.78, 1H-indole-5- 7.65 Hz, 1H), 1.64-1.77 (m, 2H), 1.44(dd, J = 4.52, 12.77 Hz, carboxamide 1H) 1-43 N-((1R,2R,4S)-7-cyano- 387¹H NMR (600 MHz, DMSO-d₆) δ 8.70-8.73 (m, 1H), 8.67 (d, 7- J = 8.57 Hz,1H), 8.18 (s, 1H), 7.92 (d, J = 7.86 Hz, 1H), 7.79 (t,azabicyclo[2.2.1]heptan- J = 7.81 Hz, 1H), 7.72 (d, J = 8.71 Hz, 1H),7.24 (d, J = 7.47 Hz, 2-yl)-1-methyl-3-(6- 1H), 4.29-4.38 (m, 2H),4.18-4.22 (m, 4H), 2.62 (s, 3H), 2.23- methyl-2-pyridinyl)-1H- 2.30 (m,1H), 1.89-1.98 (m, 1H), 1.80-1.89 (m, 1H), 1.67-1.76indazole-6-carboxamide (m, 2H), 1.57-4.64 (m, 1H) 1-44N-((1R,2R,4S)-7-cyano- 441.2 ¹H NMR (600 MHz, DMSO-d₆) δ 8.72 (d, J =5.99 Hz, 1H), 8.56 7- (d, J = 8.41 Hz, 1H), 8.40 (d, J = 8.02 Hz, 1H),8.24 (s, 1H), 8.20 azabicyclo[2.2.1]heptan- (t, J = 7.85 Hz, 1H), 7.89(d, J = 7.63 Hz, 1H), 7.80 (dd, J = 1.28, 2-yl)-1-methyl-3-(6- 8.52 Hz,1H), 4.27-4.38 (m, 2H), 4.25 (s, 3H), 4.20 (t, J = 4.87(trifluoromethyl)-2- Hz, 1H), 2.21-2.30 (m, 1H), 1.89-1.98 (m, 1H),1.80-1.88 (m, pyridinyl)-1H-indazole- 1H), 1.67-1.75 (m, 2H), 1.59 (dd,J = 4.67, 12.77 Hz, 1H) 6-carboxamide 1-45 N-((1R,2R,4S)-7-cyano- 372 ¹HNMR (600 MHz, DMSO-d₆) δ 8.74 (d, J = 5.84 Hz, 1H), 8.20 7- (s, 1H),8.15 (d, J = 8.41 Hz, 1H), 7.99 (dd, J = 1.09, 8.17 Hz, 2H),azabicyclo[2.2.1]heptan- 7.71 (dd, J = 1.32, 8.56 Hz, 1H), 7.54 (t, J =7.75 Hz, 2H), 7.43 (t, 2-yl)-1-methyl-3-phenyl- J = 7.40 Hz, 1H),4.27-4.38 (m, 2H), 4.16-4.22 (m, 4H), 2.22-2.29 1H-indazole-6- (m, 1H),1.89-1.96 (m, 1H), 1.80-1.89 (m, 1H), 1.67-1.76 (m, carboxamide 2H),1.61 (dd, J = 4.67, 12.77 Hz, 1H) 1-46 N-((1R,2R,4S)-7-cyano- 366 ¹H NMR(600 MHz, DMSO-d₆) δ 8.63 (d, J = 5.99 Hz, 1H), 7.93 7- (s, 1H), 7.83(d, J = 7.71 Hz, 1H), 7.63 (d, J = 7.63 Hz, 1H), 7.52azabicyclo[2.2.1]heptan- (t, J = 7.67 Hz, 1H), 7.27-7.39 (m, 1H), 6.92(d, J = 11.00 Hz, 1H), 2-yl-3-((3- 6.88 (d, J = 8.38 Hz, 1H), 6.78 (dt,J = 2.34, 8.49 Hz, 1H), 5.18 (s, fluorophenoxy)methyl)benzamide 2H),4.22-4.32 (m, 2H), 4.16 (t, J = 4.87 Hz, 1H), 2.17-2.23 (m, 1H),1.77-1.90 (m, 2H), 1.63-1.72 (m, 2H), 1.56 (dd, J = 4.71, 12.73 Hz, 1H)1-47 N-((1R,2R,4S)-7-cyano- 354 ¹H NMR (600 MHz, DMSO-d₆) δ 8.41 (d, J =5.99 Hz, 1H), 7.84 7- (d, J = 8.04 Hz, 2H), 7.56 (dd, J = 1.17, 5.06 Hz,1H), 7.24 (s, 1H), azabicyclo[2.2.1]heptan- 7.11 (d, J = 7.99 Hz, 2H),7.04 (dd, J = 3.46, 5.02 Hz, 1H), 5.37 (s, 2-yl)-4-(2- 2H), 4.19-4.29(m, 2H), 4.15 (t, J = 4.79 Hz, 1H), 2.15-2.22 (m,thiophenylmethoxy)benzamide 1H), 1.76-1.89 (m, 2H), 1.61-1.72 (m, 2H),1.54 (dd, J = 4.71, 12.73 Hz, 1H) 1-48 N-((1R,2R,4S)-7-cyano- 364 ¹H NMR(600 MHz, DMSO-d₆) δ 8.53 (d, J = 5.99 Hz, 1H), 7.78 7- (d, J = 7.93 Hz,2H), 7.35-7.43 (m, 3H), 7.24-7.32 (m, 1H), 7.16 azabicyclo[2.2.1]heptan-(d, J = 8.00 Hz, 2H), 4.19-4.29 (m, 2H), 4.15 (t, J = 4.79 Hz, 1H),2-yl)-4-((2- 2.31 (s, 3H), 2.15-2.22 (m, 1H), 1.76-1.87 (m, 2H),1.61-1.70 methylphenyl)sulfanyl)benzamide (m, 2H), 1.52 (dd, J = 4.67,12.69 Hz, 1H) 1-49 N-((1R,2R,4S)-7-cyano- 328.2 ¹H NMR (600 MHz,DMSO-d₆) δ 8.39 (d, J = 5.99 Hz, 1H), 7.81- 7- 7.85 (m, 2H), 6.98-7.02(m, J = 8.88 Hz, 2H), 4.18-4.29 (m, 2H), (azabicyclo[2.2.1]heptan- 4.15(t, J = 4.79 Hz, 1H), 4.05 (t, J = 6.66 Hz, 2H), 2.14-2.22 (m,2-yl)-4-(3- 1H), 1.74-1.87 (m, 3H), 1.60-1.72 (m, 4H), 1.55 (dd, J =4.67, methylbutoxy)benzamide 12.69 Hz, 1H), 0.93 (d, J = 6.70 Hz, 6H)1-50 N-((1R,2R,4S)-7-cyano- 375 ¹H NMR (600 MHz, DMSO-d₆) δ 8.64 (d, J =5.92 Hz, 1H), 7.97 7- (dd, J = 1.09, 7.71 Hz, 1H), 7.87 (d, J = 7.76 Hz,2H), 7.71 (dt, azabicyclo[2.2.1]heptan- J = 1.44, 7.77 Hz, 1H), 7.56 (t,J = 7.61 Hz, 1H), 7.40-7.49 (m, 2-yl)-4-((2- 3H), 4.21-4.31 (m, 2H),4.16 (t, J = 4.83 Hz, 1H), 2.17-2.23 (m, cyanophenyl)sulfanyl)benzamide1H), 1.77-1.89 (m, 2H), 1.62-1.71 (m, 2H), 1.53 (dd, J = 4.71, 12.81 Hz,1H) 1-51 N-((1R,2R,4S)-7-cyano- 413.2 ¹H NMR (600 MHz, DMSO-d₆) δ 8.64(d, J = 6.59 Hz, 1H), 8.60 7- (d, J = 8.91 Hz, 1H), 8.37 (s, 1H), 8.08(dd, J = 1.40, 8.87 Hz, 1H), azabicyclo[2.2.1]heptan- 7.81 (t, J = 7.89Hz, 1H), 7.69 (t, J = 8.17 Hz, 1H), 7.23 (d, J = 7.472-yl)-1-(6-cyclopropyl- Hz, 1H), 4.31-4.39 (m, 1H), 4.28 (t, J = 4.59Hz, 1H), 4.19 (t, 2-pyridinyl)-3-methyl- J = 4.90 Hz, 1H), 2.60-2.67 (m,3H), 2.20-2.28 (m, 2H), 1.88-1.97 1H-indazole-5- (m, 1H), 1.80-1.88 (m,1H), 1.66-1.76 (m, 2H), 1.60 (dd, J = 4.71, carboxamide 12.73 Hz, 1H),1.06-1.14 (m, 4H) 1-52 6-chloro-N-((1R,2R,4S)- 433 ¹H NMR (600 MHz,DMSO-d₆) δ 8.85 (d, J = 5.92 Hz, 1H), 8.76 7-cyano-7- (s, 1H), 8.53 (d,J = 0.78 Hz, 1H), 8.05 (s, 1H), 7.87 (t, J = 8.05azobicyclo[2.2.1]heptan- Hz, 1H), 7.75 (d, J = 8.46 Hz, 1H), 7.31 (d, J= 7.01 Hz, 1H), 4.25- 2-yl)-1-(6-cyclopropyl- 4.34 (m, 2H), 4.17 (t, J =4.90 Hz, 1H), 2.22-2.29 (m, 2H), 2.03 2--pyridinyl)-1H- (ddd, J = 4.09,8.99, 12.85 Hz, 1H), 1.78-1.88 (m, 1H), 1.70-1.78 indazole-5-carboxamide(m, 1H), 1.50-1.65 (m, 1H), 1.40 (dd, J = 4.16, 12.73 Hz, 1H), 1.07-1.17(m, 4H) 1-53 N-((1R,2R,4S)-7-cyano- 413.2 ¹H NMR (600 MHz, DMSO-d₆) δ8.69 (d, J = 6.07 Hz, 1H), 8.52 7- (s, 1H), 8.45 (s, 1H), 7.92 (s, 1H),7.84 (t, J = 8.14 Hz, 1H), 7.73 azabicyclo[2.2.1]heptan- (d, J = 8.29Hz, 1H), 7.26 (d, J = 7.55 Hz, 1H), 4.25-4.36 (m, 2H),2-yl)-1-(6-cyclopropyl- 4.11-4.21 (m, 1H), 2.52 (s, 3H), 2.20-2.28 (m,2H), 1.98 (ddd, 2-pyridinyl)-6-methyl- J = 4.09, 8.97, 12.79 Hz, 1H),1.78-1.87 (m, 1H), 1.70-1.78 (m, 1H-indazole-5- 1H), 1.61-1.67 (m, 1H),1.45 (dd, J = 4.48, 12.73 Hz, 1H), 1.09- carboxamide 1.16 (m, 4H) 1-545-bromo-3-chloro-N- 406.8 1H NMR (600 MHz, DMSO-d6) Shift 9.02 (d, J =6.07 Hz, 1H), ((1R,2R,4S)-7-cyano-7- 7.71-7.75 (m, 1H), 7.59-7.65 (m,1H), 7.46-7.50 (m, 1H), 4.33- azabicyclo[2.2.1]heptan- 4.39 (m, 1H),4.30-4.32 (m, 1H), 4.18 (t, J = 4.90 Hz, 1H), 2.23- 2-yl)-1-methyl-1H-2.29 (m, 1H), 2.03-2.10 (m, 1H), 1.80-1.89 (m, 1H), 1.70-1.79indole-2-carboxamide (m, 1H), 1.61-1.68 (m, 1H), 1.45-1.49 (m, 1H) 1-55Mixture of two 360.0 1H NMR (600 MHz, DMSO-d6) Shift 8.19-8.27 (m, 1H),7.38- diastereomers: (2R)-5- 7.41 (m, 1H), 7.28-7.32 (m, 1H), 7.14-7.17(m, 1H), 4.08-4.14 bromo-N-(7-cyano-7- (m, 3H), 2.93-3.27 (m, 5H),2.14-2.21 (m, 1H), 1.78-1.88 (m, azabicyclo[2.2.1]heptan- 2H), 1.55-1.71(m, 2H), 1.25-1.30 (m, 1H) 2-yl)-2,3-dihydro-1H- indene-2-carboxamideand (2S)-5-bromo-N-(7- cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2,3-dihydro-1H- indene-2-carboxamide 1-56 5-bromo-N-((1R,2R,4S)-390.0 1H NMR (600 MHz, DMSO-d6) Shift 8.63-8.72 (m, 1H), 8.11 7-cyano-7-(d, J = 1.56 Hz, 1H), 8.00 (d, J = 8.56 Hz, 1H), 7.63 (dd, J = 1.87,azabicyclo[2.2.1]heptan- 8.56 Hz, 1H), 4.28 (br d, J = 4.67 Hz, 2H),4.17 (t, J = 4.90 Hz, 2-yl)-3-methyl-1- 1H), 2.55 (s, 3H), 2.18-2.26 (m,1H), 1.63-1.93 (m, 4H), 1.46- benzothiophene-2- 1.55 (m, 1H) carboxamide1-57 N-benzyl-3-bromo-N-(2- 467.0 1H NMR (500 MHz, CHLOROFORM-d) Shift7.56-7.67 (m, (((1R,2R,4S)-7-cyano-7- 2H), 7.26-7.44 (m, 5H), 7.14-7.21(m, 2H), 6.86-6.96 (m, azabicyclo[2.2.1]heptan- 1H), 4.63-4.71 (m, 2H),4.21-4.32 (m, 2H), 3.96-4.10 (m, 2-yl)amino)-2- 3H), 2.30-2.44 (m, 1H),1.92-2.04 (m, 1H), 1.81-1.90 oxoethyl)benzamide (m, 2H), 1.45-1.58 (m,1H), 0.98-1.11 (m, 1H) 1-58 N-benzyl-3-chloro-N-(2- 423.0 1H NMR (600MHz, DMSO-d6) Shift 8.17 (br d, J = 5.84 Hz, (((1R,2R,4S)-7-cyano-7-1H), 7.19-7.57 (m, 10H), 4.44-4.70 (m, 2H), 4.02-4.18 (m, 3H),azabicyclo[2.2.1]heptan- 3.68-4.02 (m, 2H), 2.07-2.22 (m, 1H), 1.72-1.91(m, 1H), 1.40- 2-yl)amino)-2- 1.68 (m, 3H), 1.03-1.26 (m, 1H)oxoethyl)benzamide 1-59 3-bromo-N-(2- 377.0 1H NMR (600 MHz, DMSO-d6)Shift 8.81-8.91 (m, 1H), 8.24- (((1R,2R,4S)-7-cyano-7- 8.30 (m, 1H),8.03-8.09 (m, 1H), 7.84-7.89 (m, 1H), 7.72-7.78 azabicyclo[2.2.1]heptan-(m, 1H), 7.43-7.49 (m, 1H), 4.06-4.16 (m, 3H), 3.83-3.92 (m,2-yl)amino-2- 2H), 2.12-2.22 (m, 1H), 1.85-1.93 (m, 1H), 1.77-1.84 (m,1H), oxoethyl)benzamide 1.54-1.69 (m, 2H), 1.26-1.32 (m, 1H) 1-603-chloro-N-(2- 333.0 1H NMR (600 MHz, DMSO-d6) Shift 8.85-8.91 (m, 1H),8.28 (((1R,2R,4S)-7-cyano-7- (br d, J = 6.15 Hz, 1H), 7.90-7.94 (m, 1H),7.81-7.86 (m, 1H), azabicyclo[2.2.1]heptan- 7.60-7.65 (m, 1H), 7.49-7.55(m, 1H), 4.05-4.16 (m, 3H), 3.89 2-yl)amino)-2- (d, J = 5.84 Hz, 2H),2.13-2.22 (m, 1H), 1.86-1.93 (m, 1H), 1.76- oxoethyl)benzamide 1.85 (m,1H), 1.55-1.68 (m, 2H), 1.29 (dd, J = 4.52, 12.69 Hz, 1H) 1-61 Mixtureof two 359.0 1H NMR (600 MHz, DMSO-d6) Shift 8.38-8.48 (m, 1H), 7.82-diastereomers: (3R)-1- 7.90 (m, 1H), 7.52-7.59 (m, 1H), 7.36-7.43 (m,1H), 7.17-7.23 (3-chlorophenyl)-N-(7- (m, 1H), 4.07-4.18 (m, 3H),3.98-4.07 (m, 1H), 3.83-3.90 (m, cyano-7- 1H), 3.27 (br s, 1H), 3.17 (d,J = 5.14 Hz, 1H), 2.76 (br dd, azabicyclo[2.2.1]heptan- J = 9.42, 12.85Hz, 1H), 2.67 (br dd, J = 6.93, 8.49 Hz, 1H), 213- 2-yl)-5-oxo-3- 2.24(m, 1H), 1.77-1.90 (m, 2H), 1.55-1.70 (m, 2H), 1.20-1.30pyrrolidinecarboxamide, (m, 1H) and (3S)-1-(3- chlorophenyl)-N-(7-cyano-7- azabicyclo[2.2.1]heptan- 2-yl)-5-oxo-3- pyrrolidinecarboxamide1-62 Mixture of two 403.0 1H NMR (600 MHz, DMSO-d6) Shift 8.40-8.44 (m,1H), 7.99- diastereomers: (3R)-1- 8.02 (m, 1H), 7.56-7.60 (m, 1H),7.32-7.36 (m, 2H), 4.08-4.17 (3-bromophenyl)-N-(7- (m, 3H), 3.99-4.05(m, 1H), 3.86 (ddd, J = 5.80, 9.75, 17.93 Hz, cyano-7- 1H), 3.22-3.30(m, 1H), 2.77 (ddd, J = 9.42, 12.67, 16.99 Hz, 1H),azabicyclo[2.2.1]heptan- 2.62-2.69 (m, 1H), 2.15-2.25 (m, 1H), 1.78-1.90(m, 2H), 1.55- 2-yl)-5-oxo-3- 1.70 (m, 2H), 1.22-4.29 (m, 1H)pyrrolidinecarboxamide, and (3S)-1-(3- bromophenyl)-N-(7- cyano-7-azabicyclo[2.2.1]heptan- 2-yl)-5-oxo-3- pyrrolidinecarboxamide 1-63Mixture of two 359.0 1H NMR (600 MHz, DMSO-d6) Shift 8.51-8.61 (m, 1H),7.81- diastereomers: (3R)-1- 7.88 (m, 1H), 7.53-7.61 (m, 1H), 7.40-7.45(m, 1H), 7.19-7.26 (3-chlorophenyl)-N-(7- (m, 1H), 4.04-4.20 (m, 3H),3.81-3.95 (m, 2H), 3.53-3.60 (m, cyano-7- 1H), 2.15-2.37 (m, 3H),2.03-2.12 (m, 1H), 1.78-2.11 (m, 1H), azabicyclo[2.2.1]heptan- 1.77-1.91(m, 1H), 1.56-1.70 (m, 2H), 1.24-1.37 (m, 1H) 2-yl)-2-oxo-3-pyrrolidinecarboxamide, and (3S)-1-(3- chlorophenyl)-N-(7- cyano-7-azabicyclo[2.2.1]heptan- 2-yl)-2-oxo-3- pyrrolidinecarboxamide 1-642-(3-chlorophenyl)-N- 359.0 1H NMR (600 MHz, DMSO-d6) Shift 8.63-8.70(m, 1H), 8.38- ((1R,2R,4S)-7-cyano-7- 8.42 (m, 1H), 8.18 (t, J = 1.67Hz, 1H), 7.99-8.03 (m, 1H), 7.55- azabicyclo[2.2.1]heptan- 7.64 (m, 2H),4.25-4.34 (m, 2H), 4.16-4.21 (m, 1H), 2.18-2.26 2-yl)-1,3-thiazole-4-(m, 1H), 1.65-1.91 (m, 5H) carboxamide 2-1-1 2-(4-chloro-3- 374 ¹H NMR(500 MHz, DMSO-d₆) δ 8.42 (br d, J = 5.58 Hz, 1H),(trifluoromethyl)phenoxy)- 7.65 (d, J = 8.82 Hz, 1H), 7.38 (d, J = 2.98Hz, 1H), 7.28 (dd, N-((endo)-7-cyano-7- J = 3.05, 8.89 Hz, 1H),4.64-4.71 (m, 2H), 4.10-4.16 (m, 3H), azabicyclo[2.2.1]heptan- 2.13-2.20(m, 1H), 1.74-1.83 (m, 2H), 1.55-1.67 (m, 2H), 1.36 2-yl)acetamide (dd,J = 4.15, 12.85 Hz, 1H) enantiomer 1 2-1-2 2-(4-chloro-3- 374 ¹H NMR(500 MHz, DMSO-d₆) δ 8.42 (br d, J = 5.58 Hz, 1H),(trifluoromethy)phenoxy)- 7.65 (d, J = 8.82 Hz, 1H), 7.38 (d, J = 2.98Hz, 1H), 7.28 (dd, N-((endo)-7-cyano-7- J = 3.05, 8.89 Hz, 1H),4.64-4.71 (m, 2H), 4.10-4.16 (m, 3H), azabicyclo[2.2.1]heptan- 2.13-2.20(m, 1H), 1.74-1.83 (m, 2H), 1.55-1.67 (m, 2H), 1.36 2-yl)acetamide (dd,J = 4.15, 12.85 Hz, 1H) enantiomer 2 3-1-1 3-(3-chlorophenyl)-N- 343.161H NMR (500 MHz, DMSO-d6) δ 9.30 (d, J = 6.23 Hz, 1H), 8.01((endo)-7-cyano-7- (t, J = 1.69 Hz, 1H), 7.92 (d, J = 7.41 Hz, 1H), 7.77(s, 1H), 7.56- azabicyclo[2.2.1]heptan- 7.64 (m, 2H), 4.22-4.33 (m 2H),4.18 (t, J = 4.80 Hz, 1H), 3.32 2-yl)-1,2-oxazole-5- (s, 15H), 2.17-2.25(m, 1H), 1.85-1.92 (m, 1H), 1.77-1.85 (m, carboxamide enantiomer 1 1H),1.64-1.74 (m, 2H), 1.62 (dd, J = 4.67, 12.85 Hz, 1H) 3-1-23-(3-chlorophenyl)-N- 343.16 1H NMR (500 MHz, DMSO-d6) δ 9.30 (d, J =6.23 Hz, 1H), 8.01 ((endo)-7-cyano-7- (t, J = 1.69 Hz, 1H), 7.92 (d, J =7.41 Hz, 1H), 7.77 (s, 1H), 7.56- azabicyclo[2.2.1]heptan- 7.64 (m, 2H),4.22-4.33 (m, 2H), 4.18 (t, J = 4.80 Hz, 1H), 3.32 2-yl)-1,2-oxazole-5-(s, 15H), 2.17-2.25 (m, 1H), 1.85-1.92 (m, 1H), 1.77-1.85 (m,carboxamide enantiomer2 1H), 1.64-1.74 (m, 2H), 1.62 (dd, J = 4.67,12.85 Hz, 1H) 3-3 Racemic, endo 2-((4- 373 chloro-3-(trifluromethyl)phenyl) amino)-N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)acetamide 3-7 Racemic, endo 3-bromo- 390.9 N-(1-(7-cyano-7-azabicyclo[2.2.1]heptan- 2-yl)amino)-1- oxopropan-2- yl)benzamide 3-8Racemic, endo 3-bromo- 405 N-(1-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)amino)-2-methyl-1- oxopropan-2- yl)benzamide 4-1-1(endo)-7-cyano-N-(4-(3- 393 ¹H NMR (500 MHz, DMSO-d₆) δ 8.23 (s, 1H),8.19 (br t, J = 3.57 (trifluoromethyl)phenyl)- Hz, 1H), 7.86 (s, 1H),7.63-7.69 (m, 2H), 4.47 (t, J = 4.74 Hz, 1,3-thiazol-2-yl)-7- 1H), 4.22(t, J = 4.28 Hz, 1H), 3.30-3.49 (m, 1H), 1.93-2.05 (m,azabicyclo[2.2.1]heptane- 2H), 1.76-1.85 (m, 1H), 1.64-1.76 (m, 1H),1.46-1.57 (m, 2H) 2-carboxamide 4-1-2 (endo)-7-cyano-N-(4-(3- 393 ¹H NMR(500 MHz, DMSO-d₆) δ 8.23 (s, 1H), 8.19 (br t, J = 3.57(trifluoromethyl)phenyl)- Hz, 1H), 7.86 (s, 1H), 7.63-7.69 (m, 2H), 4.47(t, J = 4.74 Hz, 1,3-thiazol-2-yl)-7- 1H), 4.22 (t, J = 4.28 Hz, 1H),3.30-3.49 (m, 1H), 1.93-2.05 (m, azabicyclo[2.2.1]heptane- 2H),1.76-1.85 (m, 1H), 1.64-1.76 (m, 1H), 1.46-1.57 (m, 2H) 2-carboxamide4-1-3 (exo)-7-cyano-N-(4-(3- 393 ¹H NMR (500 MHz, DMSO-d₆) δ 8.24 (s,1H), 8.17-8.22 (m, (trifluoromethyl)phenyl)- 1H), 7.83 (s, 1H), 7.66 (d,J = 4.89 Hz, 2H), 4.44 (d, J = 4.54 Hz, 1,3-thiazol-2-yl)-7- 1H), 4.22(t, J = 4.48 Hz, 1H), 2.89 (dd, J = 5.13, 9.02 Hz, 1H),azabicyclo[2.2.1]heptane- 2.15-2.26 (m, 1H), 1.72-1.90 (m, 3H),1.62-1.71 (m, 1H), 1.51- 2-carboxamide 1.62 (m, 1H) 4-1-4(exo)-7-cyano-N-(4-(3- 393 ¹H NMR (500 MHz, DMSO-d₆) δ 8.24 (s, 1H),8.17-8.22 (m, (trifluoromethyl)phenyl)- 1H), 7.83 (s, 1H), 7.66 (d, J =4.89 Hz, 2H), 4.44 (d, J = 4.54 Hz, 1,3-thiazol-2-yl)-7- 1H), 4.22 (t, J= 4.48 Hz, 1H), 2.89 (dd, J = 5.13, 9.02 Hz, 1H),azabicyclo[2.2.1]heptane- 2.15-2.26 (m, 1H), 1.72-1.90 (m, 3H),1.62-1.71 (m, 1H), 1.51- 2-carboxamide 1.62 (m, 1H) 4-2-1(endo)-2-((5-(2-fluoro-5- 376 methylphenyl)-2,3- dihydro-1H-indol-1-yl)carbonyl)-7- azabicyclo[2.2.1]heptane- 7-carbonitrile 4-2-2(endo)-2-((5-(2-fluoro-5- 376 1H NMR (600 MHz, DMSO-d6) δ 8.10 (d, J =8.41 Hz, 1H), 7.37 methylphenyl)-2,3- (s, 1H, 7.28 (d, J = 8.52 Hz, 1H),7.24 (d, J = 8.14 Hz, 1H), 7.11 dihydro-1H-indol-1- (s, 1H), 7.10 (s,1H), 4.55 (t, J = 4.32 Hz, 1H), 4.24 (t, J = 8.49 Hz, yl)carbonyl)-7-2H), 4.18 (t, J = 4.87 Hz, 1H), 3.39-3.45 (m, 1H), 3.15 (br t,azabicyclo[2.2.1]heptane- J = 8.41 Hz, 2H), 3.11 (br s, 1H), 2.27 (s,3H), 1.97-2.03 (m, 1H), 7-carbonitrile 1.88-1.97 (m, 1H), 1.71-1.81 (m,1H), 1.56-1.66 (m, 2H), 1.50- 1.56 (m, 1H) 4-2-3(exo)-2-((5-(2-fluoro-5- 376.2 methylphenyl)-2,3- dihydro-1H-indol-1-yl)carbonyl)-7- azabicyclo[2.2.1]heptane- 7-carbonitrile 4-2-4(exo)-2-((5-(2-fluoro-5- 376.2 1H NMR (600 MHz, DMSO-d6) δ 8.08 (d, J =8.33 Hz, 1H), 7.37 methylphenyl)-2,3- (s, 1H), 7.30 (d, J = 8.39 Hz,1H), 7.26 (d, J = 7.69 Hz, 1H), 7.12 dihydro-1H-indol-1- (d, J = 7.90Hz, 2H), 4.38-4.47 (m, 1H), 4.19 (br s, 1H), 4.09-4.17 yl)carbonyl)-7-(m, 1H), 4.02-4.09 (m, 1H), 3.10-3.21 (m, 2H), 2.95 (br dd,azabicyclo[2.2.1]heptane- J = 5.37, 8.88 Hz, 1H), 2.29 (s, 3H),2.00-2.11 (m, 1H), 1.85 (br 7-carbonitrile dd, J = 9.23, 11.87 Hz, 1H),1.76-1.83 (m, 2H), 1.67 (br t, J = 8.64 Hz, 1H), 1.53-1.62 (m, 1H) 5-1Racemic, endo N-(7- 389 ¹H NMR (500 MHz, DMSO-d₆) δ 8.42 (d, J = 9.08Hz, 1H), 8.36 cyano-7- (d, J = 6.10 Hz, 1H), 7.74 (s, 1H), 7.75 (d, J =6.32 Hz, 1H), 6.74 azabicyclo[2.2.1]heptan- (s, 1H), 4.26-4.32 (m, 1H),4.20-4.25 (m, 3H), 4.13-4.19 (m, 2-yl)-1-(4,6-dimethyl-2- 1H), 3.18 (t,J = 8.69 Hz, 2H), 2.36-2.43 (m, 6H), 2.19 (br s, 1H), pyrimidinyl)-2,3-1.77-1.89 (m, 2H), 1.62-1.72 (m, 2H), 1.56 (dd, J = 4.80, 12.85dihydro-1H-indole-5- Hz, 1H) carboxamide 5-2 Racemic, endo N-(7- 400.2¹H NMR (500 MHz, DMSO-d₆) δ 8.29 (d, J = 6.10 Hz, 1H), 8.23 cyano-7- (d,J = 8.43 Hz, 1H), 7.73 (d, J = 8.45 Hz, 1H), 7.70 (s, 1H), 7.58azabicyclo[2,2,1]hteptan- (t, J = 7.85 Hz, 1H), 6.87 (d, J = 7.40 Hz,1H), 6.62 (d, J = 8.30 Hz, 2-yl)-1-(6-cyclopropyl- 1H), 4.13-4.32 (m,3H), 4.03 (t, J = 8.76 Hz, 2H), 3.18-3.28 (m, 2-pyridinyl)-2,3- 2H),2.15-2.25 (m, 1H), 2.05-2.11 (m, 1H), 1.77-1.92 (m, 2H),dihydro-1H-indole-5- 1.61-1.73 (m, 2H), 1.57 (dd, J = 4.74, 12.78 Hz,1H), 0.93-1.11 carboxamide (m, 4H) 5-3 Racemic, endo N-(7- 401.3 ¹H NMR(500 MHz, DMSO-d₆) δ 8.34 (d, J = 6.10 Hz, 1H), 8.16 cyano-7- (d, J =8.50 Hz, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7.77 (d, J = 8.68azabicyclo[2.2.1]heptan- Hz, 1H), 7.74 (s, 1H), 4.29 (br dd, J = 4.87,10.96 Hz, 1H), 4.12- 2-yl)-1-(6-cyclopropyl- 4.23 (m, 4H), 3.23-3.29 (m,2H), 2.13-2.23 (m, 2H), 1.77-1.90 2-pyrazinyl)-2,3- (m, 2H), 1.62-1.73(m, 2H), 1.57 (dd, J = 4.67, 12.72 Hz, 1H), dihydro-1H-indole-5-1.00-1.10 (m, 4H) carboxamide 5-4 Racemic, endo N-(7- 399.2 ¹H NMR (600MHz, DMSO-d₆) δ 8.22-8.33 (m, 1H), 7.70 (s, cyano-7- 1H), 7.64 (d, J =8.52 Hz, 1H), 7.24 (t, J = 7.86 Hz, 1H), 6.95-7.09azobicyclo[2.2.1]heptan- (m, 3H), 6.73 (d, J = 7.63 Hz, 1H), 4.17-4.30(m, 2H), 4.14 (t, 2-yl)-1-(3- J = 4.71 Hz, 1H), 4.01 (t, J = 8.68 Hz,2H), 3.10-3.17 (m, 2H), cyclopropylphenyl)-2,3- 2.14-2.21 (m, 1H),1.90-1.97 (m, 1H), 1.76-1.88 (m, 2H), 1.60- dihydro-1H-indole-5- 1.72(m, 2H), 1.56 (dd, J = 4.71, 12.65 Hz, 1H), 0.91-0.99 (m, carboxamide2H), 0.66-0.73 (m, 2H) 5-5 Racemic, endo N-(7- 400.2 ¹H NMR (600 MHz,DMSO-d₆) δ 8.32 (d, J = 6.56 Hz, 1H), 8.28 cyano-7- (d, J = 8.68 Hz,1H), 8.15 (d, J = 5.22 Hz, 1H), 7.71 (s, 1H), 7.68azabicyclo[2.2.1]heptan- (d, J = 8.46 Hz, 1H), 6.63 (s, 1H), 6.58 (dd,,J = 0.93, 5.22 Hz, 1H), 2-yl)-1-(4-cyclopropyl- 4.19-4.30 (m, 2H), 4.15(t, J = 4.83 Hz, 1H), 4.08 (t, J = 8.76 Hz, 2-pyridinyl)-2,3- 2H),3.16-3.29 (m, 2H), 2.15-2.22 (m, 1H), 1.92-1.98 (m, 1H),dihydro-1H-indole-5- 1.77-1.89 (m, 2H), 1.62-1.73 (m, 2H), 1.56 (dd, J =4.75, 12.69 carboxamide Hz, 1H ) 0.97-1.09 (m, 2H), 0.78-0.89 (m, 2H)5-6 Racemic, endo N-(7- 391.2 ¹H NMR (600 MHz, DMSO-d₆) δ 8.38 (d, J =5.99 Hz, 1H), 8.34 cyano-7- (s, 1H), 8.33 (s, 1H), 7.74-7.80 (m, 2H),6.40 (d, J = 5.61 Hz, azabicyclo[2.2.1]heptan- 1H), 4.20-4.31 (m, 4H),4.16 (t, J = 4.87 Hz, 1H), 3.99 (s, 3H), 2-yl)-1-(4-methoxy 2- 3.16-3.25(m, 2H), 2.16-2.22 (m, 1H), 1.77-1.90 (m, 2H), 1.63- pyrimidinyl)-2,3-1.73 (m, 2H), 1.57 (dd, J = 4.75, 12.69 Hz, 1H) dihydro-1H-indole-5-carboxamide 5-7 Racemic, endo N-(7- 429.2 ¹H NMR (600 MHz, DMSO-d₆) δ8.97 (d, J = 4.83 Hz, 1H), 8.41 cyano-7- (d, J = 6.86 Hz, 1H), 8.30 (d,J = 9.03 Hz, 1H), 7.80 (s, 1H), 7.81 azabicyclo[2.2.1]heptan- (d, J =7.04 Hz, 1H), 7.39 (d, J = 4.90 Hz, 1H), 4.25-4.32 (m, 3H), 2-yl)-1-(4-4.14-4.25 (m, 2H), 3.23-3.30 (m, 2H), 2.16-2.23 (m, 1H), 1.77-(trifluoromethyl)-2- 1.91 (m, 2H), 1.63-1.73 (m, 2H), 1.53-1.60 (m, 1H)pyrimidinyl)-2,3- dihydro-1H-indole-5- carboxamide 5-8 Racemic, endoN-(7- 417.2 ¹H NMR (500 MHz, DMSO-d₆) δ 8.54 (d, J = 5.19 Hz, 1H), 8.40cyano-7- (d, J = 8.28 Hz, 1H), 8.37 (d, J = 5.74 Hz, 1H), 7.78 (d, J =8.49 Hz, azabicyclo[2.2.1]heptan- 1H), 7.75 (s, 1H), 7.00 (d, J = 5.32Hz, 1H), 4.20-4.32 (m, 4H), 2-yl)-1-(4-(2-methyl-2- 4.16 (t, J = 4.87Hz, 1H), 3.21 (t, J = 8.76 Hz, 2H), 2.15-2.22 (m, propanyl)-2- 1H),1.77-1.90 (m, 2H), 1.62-1.72 (m, 2H), 1.57 (dd, J = 4.67,pyrimidinyl)-2,3- 12.72 Hz, 1H), 1.34 (s, 9H) dihydro-1H-indole-5-carboxamide 5-9 Racemic, endo N-(7- 403 ¹H NMR (500 MHz, DMSO-d₆) δ 8.50(d, J = 5.06 Hz, 1H), 8.40 cyano-7- (d, J = 8.34 Hz, 1H), 8.35 (d, J =6.23 Hz, 1H), 7.77 (d, J = 8.33 Hz, azabicyclo[2.2.1]heptan- 1H), 7.75(s, 1H), 6.88 (d, J = 5.06 Hz, 1H), 4.20-4.31 (m, 4H),2-yl)-1-(4-(2-propanyl)- 4.15 (t, J = 4.80 Hz, 1H), 3.18-3.26 (m, 2H),2.97 (quin, J = 6.88 2-pyrimidinyl)-2,3- Hz, 1H), 2.16-2.23 (m, 1H),1.77-1.90 (m, 2H), 1.62-1.73 (m, dihydro-1H-indole-5- 2H), 1.57 (dd, J =4.67, 12.72 Hz, 1H), 1.28 (d, J = 6.88 Hz, 6H) carboxamide 5-10N-((1R,2R,4S)-7-cyano- 389.2 ¹H NMR (500 MHz, DMSO-d₆) δ 8.49 (d, J =5.06 Hz, 1H), 8.33- 7- 8.44 (m, 2H), 7.75 (s, 1H), 7.76 (d, J = 6.54 Hz,1H), 6.86 (d, azabicyclo[2.2.1]heptan- J = 5.06 Hz, 1H), 4.20-4.32 (m,4H), 4.15 (t, J = 4.80 Hz, 1H), 2-yl)-1-(4-ethyl-2- 3.18-3.25 (m, 2H),2.69-2.79 (m, 2H), 2.16-2.23 (m, 1H), 1.77- pyrimidinyl)-2,3- 1.91 (m,2H), 1.62-1.73 (m, 2H), 1.57 (dd, J = 4.67, 12.72 Hz,dihydro-1H-indole-5- 1H), 1.28 (t, J = 7.59 Hz, 3H) carboxamide 5-11N-((1R,2R,4S)-7-cyano- 386.2 ¹H NMR (500 MHz, DMSO-d₆) δ 8.92 (d, J =4.80 Hz, 1H), 8.43 7- (d, J = 5.97 Hz, 1H), 8.26 (d, J = 8.43 Hz, 1H),7.78-7.83 (m, 2H), azabicyclo[2.2.1]heptan- 7.51 (d, J = 4.80 Hz, 1H),4.21-4.32 (m, 4H), 4.16 (t, J = 4.74 Hz, 2-yl)-1-(4-cyano-2- 1H), 3.25(br t, J = 8.63 Hz, 2H), 2.17-2.24 (m, 1H), 1.77-1.92 pyrimidinyl)-2,3-(m, 2H), 1.63-1.73 (m, 2H), 1.57 (dd, J = 4.80, 12.72 Hz, 1H)dihydro-1H-indole-5- carboxamide 5-12 N-((1R,2R,4S)-7-cyano- 400.2 ¹HNMR (600 MHz, DMSO-d₆) δ 8.42 (d, J = 6.07 Hz, 1H), 8.22- 7- 8.36 (m,1H), 7.75-7.84 (m, 2H), 7.44 (s, 1H), 4.20-4.32 (m,azabicyclo[2.2.1]heptan- 4H), 4.11-4.20 (m, 1H), 3.23 (br t, J = 8.68Hz, 2H), 2.52-2.55 (s, 2-yl)-1-(4-cyano-6- 3H), 2.16-2.24 (m 1H),1.76-1.91 (m, 2H), 1.62-1.74 (m, 2H), methyl-2-pyrimidinyl)- 1.56 (br d,J = 12.69 Hz, 1H), 1.57 (br d, J = 12.77 Hz, 1H) 2,3-dihydro-1H-indole-5-carboxamide 5-13 N-((1R,2R,4S)-7-cyano- 411.2 ¹H NMR (600 MHz,DMSO-d₆) δ 8.85 (d, J = 4.91 Hz, 1H), 8.41 7- (d, J = 6.07 Hz, 1H), 8.36(d, J = 8.33 Hz, 1H), 7.80 (s, 1H), 7.79 azabicyclo[2.2.1]heptan- (d, J= 10.62 Hz, 1H), 7.19 (d, J = 4.90 Hz, 1H), 6.96 (J = 54.42 2-yl)-1-(4-Hz, 1H), 4.21-4.33 (m, 4H), 4.16 (t, J = 4.87 Hz, 1H), 3.25 (br t,(difluoromethyl)-2- J = 8.60 Hz, 2H), 2.17-2.23 (m, 1H), 1.77-1.91 (m,2H), 1.62-1.75 pyrimidinyl)-2,3- (m, 2H), 1.57 (dd, J = 4.67, 12.69 Hz.1H) dihydro-1H-indole-5- carboxamide 5-14 N-((1R,2R,4S)-7-cyano- 443.2¹H NMR (600 MHz, DMSO-d₆) δ 8.40 (d, J = 6.07 Hz, 1H), 8.34 7- (br d, J= 7.86 Hz, 1H), 7.80 (d, J = 10.28 Hz, 1H), 7.79 (s, 1H),azabicyclo[2.2.1]heptan- 7.33 (s, 1H), 4.21-4.32 (m, 4H), 4.14-4.19 (m,1H), 3.24 (br t, 2yl)-1-(4-methyl-6- J = 8.64 Hz, 2H), 2.52-2.58 (m,3H), 2.17-2.24 (m, 1H), 1.78-1.93 (trifluoromethyl)-2- (m, 2H),1.63-1.73 (m, 2H), 1.54-1.61 (m, 1H) pyrimidinyl)-2,3-dihydro-1H-indole-5- carboxamide 5-15 N-((1R,2R,4S)-7-cyano- 392.2 ¹HNMR (500 MHz, DMSO-d₆) δ 8.31 (d, J = 5.97 Hz, 1H), 7.73 7- (s, 1H),7.66 (dd, J = 1.82, 8.43 Hz, 1H), 7.61 (dd, J = 8.11, 12.39azabicyclo[2.2.1]heptan- Hz, 1H), 7.30 (dd, J = 2.85, 8.43 Hz, 1H), 6.95(dd, J = 2.79, 8.11 2-yl)-1-(3-fluoro-6- Hz, 1H), 4.28 (br dd, J = 4.80,11.03 Hz, 1H), 4.17-4.23 (m, 4H), methyl-2-pyridinyl)-2,3- 3.17 (s, 2H),2.40 (s, 3H), 2.14-2.25 (m, 1H), 1.83-1.88 (m, 1H), dihydro-1H-indole-5-1.79-1.82 (m, 1H), 1.64-1.71 (m, 2H), 1.56 (dd, J = 4.74, 12.65carboxamide Hz, 1H) 6-1 Racemic, endo N-(7- 373.2 ¹H NMR (400 MHz,DMSO-d₆) δ 8.81 (d, J = 8.81 Hz, 1H), 8.74 cyano-7- (d, J = 5.08 Hz,1H), 8.57 (d, J = 5.91 Hz, 1H), 8.36 (d, J = 3.63 Hz,azobicyclo[2.2.1]heptan- 1H), 8.21 (d, J = 1.66 Hz, 1H), 7.84 (dd, J =1.76, 8.81 Hz, 1H), 2-yl)-1-(4-methyl-2- 7.28 (d, J = 4.98 Hz, 1H), 6.90(d, J = 3.63 Hz, 1H), 4.34 (br dd, pyrimidinyl)-1H-indole- J = 4.72,11.14 Hz, 1H), 4.26 (t, J = 4.51 Hz, 1H), 4.17 (t, J = 4.725-carboxamide Hz, 1H), 2.59 (s, 3H), 2.23 (br s, 1H), 1.87-1.96 (m, 1H),1.78- 1.86 (m, 1H), 1.66-1.75 (m, 2H), 1.60 (dd, J = 4.72, 12.80 Hz, 1H)6-2 Racemic, endo N-(7- 361.2 ¹H NMR (500 MHz, DMSO-d₆) δ 8.63 (d, J =4.80 Hz, 2H), 8.39 cyano-7- (d, J = 6.49 Hz, 1H), 8.34 (d, J = 8.38 Hz,1H), 7.72-7.79 (m, 2H), azobicyclo[2.2.1]heptan- 6.96 (t, J = 4.80 Hz,1H), 4.21-4.31 (m, 4H), 4.16 (t, J = 4.74 Hz, 2-yl)-1-(2-pyrimidinyl)-1H), 3.22 (t, J = 8.76 Hz, 2H), 2.16-2.23 (m, 1H), 1.77-1.90 (m,2,3-dihydro-1H-indole- 2H), 1.63-1.73 (m, 2H), 1.57 (dd, J = 4.67, 12.72Hz, 1H) 5-carboxamide 6-3 Racemic, endo N-(7- 375.2 ¹H NMR (500 MHz,DMSO-d₆) δ 8.49 (s, 2H), 8.36 (d, J = 5.84 cyano-7- Hz, 1H), 8.29 (d, J= 8.30 Hz, 1H), 7.72-7.77 (m, 2H), 4.13-4.31 azobicyclo[2.2.1]heptan-(m, 5H), 3.16-3.24 (m, 2H), 2.20 (s, 4H), 1.77-1.90 (m, 2H),2-yl)-1-(5-methyl-2- 1.62-1.73 (m, 2H), 1.57 (dd, J = 4.61, 12.65 Hz,1H) pyrimidinyl)-2,3- dihydro-1H-indole-5- carboxamide 7-1N-((1R,2R,4S)-7-cyano- 415.3 ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (d, J =5.08 Hz, 1H), 8.24 7- (d, J = 8.19 Hz, 1H), 7.34 (s, 1H), 7.33 (d, J =9.57 Hz, 1H), 6.89 azabicyclo[2.2.1]heptan- (d, J = 5.08 Hz, 1H), 4.46(t, J = 4.30 Hz, 1H), 4.14-4.23 (m, 4H), 2-yl)-1-(4-cyclopropyl- 3.17(t, J = 8.81 Hz, 2H), 2.96 (s, 3H), 2.04-2.22 (m, 2H), 1.81-2-pyrimidinyl)-N- 1.90 (m, 2H), 1.66-1.75 (m, 2H), 1.05-1.14 (m, 4H)methyl-2,3-dihydro-1H- indole-5-carboxamide 7-2 N-((1S,2S,4R)-7-cyano-415.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (d, J = 5.08 Hz, 1H), 8.24 7- (d,J = 8.19 Hz, 1H), 7.34 (s, 1H), 7.33 (d, J = 9.60 Hz, 1H), 6.89azabicyclo[2.2.1]heptan- (d, J = 5.18 Hz, 1H), 4.46 (t, J = 4.35 Hz,1H), 4.15-4.23 (m, 4H), 2-yl)-1-(4-cyclopropyl- 3.17 (t, J = 8.71 Hz,2H), 2.96 (s, 3H), 2.13-2.22 (m, 1H), 2.04- 2-pyrimidinyl)-N- 2.11 (m,1H), 1.80-1.89 (m, 2H), 1.64-1.75 (m, 3H), 1.05-1.15methyl-2,3-dihydro-1H- (m, 4H) indole-5-carboxamide (peak 2 derived) 8-1Racemic, endo N~5~-(7- 366.2 ¹H NMR (600 MHz, DMSO-d₆) δ 8.32 (d, J =6.07 Hz, 1H), 7.86 cyano-7- (d, J = 8.33 Hz, 1H), 7.66 (s, 1H), 7.65 (d,J = 7.10 Hz, 1H), 6.84 azabicyclo[2.2.1]heptan- (d, J = 2.65 Hz, 1H),4.23-4.29 (m, 1H), 4.20 (t, J = 4.48 Hz, 1H), 2-yl)-N~1~-cyclopropyl-4.14 (t, J = 4.79 Hz, 1H), 3.87 (t, J = 8.80 Hz, 2H), 3.12 (t, J = 8.762,3-dihydro-1H-indole- Hz, 2H), 2.59 (tdd, J = 3.56, 6.99, 10.41 Hz,1H), 2.14-2.20 (m, 1,5-dicarboxamide 1H), 1.76-1.87 (m, 2H), 1.61-1.71(m, 2H), 1.55 (dd, J = 4.67, 12.69 Hz, 1H), 0.58-0.64 (m, 2H), 0.47-0.53(m, 2H) 8-2 Racemic, endo 1-(7- 325.2 ¹H NMR (600 MHz, DMSO-d₆) δ 8.78(s, 1H), 7.55-7.61 (m, cyano-7- 4H), 6.79 (d, J = 6.53 Hz, 1H),4.02-4.22 (m, 3H), 2.21-2.30 (m, azabicyclo[2.2.1]heptan- 1H), 1.79-1.95(m, 2H), 1.66-1.76 (m, 1H), 1.54-1.66 (m, 1H), 2-yl)-3-(4- 1.10-1.22 (m,1H) (trifluoromethyl)phenyl) urea 9-1 N-((1R,2R,4S)-7-cyano- 336.2 ¹HNMR (500 MHz, DMSO-d₆) δ 8.49 (d, J = 5.97 Hz, 1H), 8.04 7- (s, 1H),7.76 (s, 1H), 7.74 (s, 1H), 7.69 (dd, J = 1.62, 7.98 Hz,azabicyclo[2.2.1]heptan- 1H), 7.49 (d, J = 8.04 Hz, 1H), 4.22-4.33 (m,2H), 4.16 (t, J = 4.74 2-yl)-3-methyl-4-(1- Hz, 1H), 3.90 (s, 3H), 2.44(s, 3H), 2.17-2.24 (m, 1H), 1.77-1.90 methyl-1H-pyrazol-4- (m, 2H),1.63-1.73 (m, 2H), 1.57 (dd, J = 4.67, 12.72 Hz, 1H) yl)benzamide 9-2N-((1R,2R,4S)-7-cyano- 392.0 ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.04(s, 1 H), 7- 7.99 (s, 1 H), 7.58 (d, J = 7.91 Hz, 1 H), 7.43 (d, J =1.56 Hz, 1 H), azabicyclo[2.2.1]heptan- 7.21 (dd, J = 7.91, 1.69 Hz, 1H), 6.17 (br d, J = 4.54 Hz, 1 H), 2-yl)-3- 4.46-4.52 (m, 2 H), 4.11 (t,J = 5.00 Hz, 1H), 3.96-4.00 (m, 3 (cyclopropylmethoxy)-4- H), 2.56 (ddd,J = 4.90, 3.15, 1.43 Hz, 1 H), 2.04-2.13 (m, 1 H),(1-methyl-1H-pyrazol-4- 1.88-1.99 (m, 2 H), 1.53-1.73 (m, 3 H),1.31-1.50 (m, 1 H), yl)benzamide 1.17 (dd, J = 13.04, 4.09 Hz, 1 H),0.67-0.75 (m, 2 H), 0.36- 0.46 (m, 2 H) 9-3 N-((1R,2R,4S)-7-cyano- 380.0¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.94 (d, J = 5.19 7- Hz, 2 H), 7.56(d, J = 7.92 Hz, 1H), 7.47 (d, J = 1.43 Hz, 1 H),azabicyclo[2.2.1]heptan- 7.19-7.26 (m, 1H), 6.23 (br d, J = 4.80 Hz, 1H), 4.45-4.53 (m, 2-yl)-4-(1-methyl-1H- 2 H), 4.08-4.13 (m, 3 H), 4.01(s, 1 H), 3.96 (s, 3 H), 2.48- pyrazol-4-yl)-3- 2.63 (m, 1H), 2.02-2.14(m, 1 H), 1.80-1.98 (m, 5 H), 1.58- propoxybenzamide 1.78 (m, 1 H), 1.19(dd, J = 12.98, 4.02 Hz, 1 H), 1.10 (t, J = 7.46 Hz, 3 H) 9-4N-((1R,2R,4S)-7-cyano- 366.0 ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.92(s, 2 H), 7- 7.53 (d, J = 7.92 Hz, 1 H), 7.45 (d, J = 1.56 Hz, 1H),7.23-7.27 azabicyclo[2.2.1]heptan- (m, 1 H), 6.59 (br d, J = 5.06 Hz,1H), 4.43-4.50 (m, 2H), 4.18 2-yl)-3-ethoxy-4-(1- (q, J = 6.92 Hz, 2 H),4.08 (t, J = 5.00 Hz, 1 H), 3.94 (s, 3 H), 2.60 methyl-1H-pyrazol-4- (s,2 H), 2.45-2.53 (m, 1 H), 1.98-2.17 (m, 1 H), 1.85-1.98 yl)benzamide (m,2 H), 1.59-1.69 (m, 2 H), 1.52 (t, J = 6.94 Hz, 3 H), 1.23- 1.28 (m, 1H) 9-5 N-((1R,2R,4S)-7-cyano- 380.0 ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm7.94 (s, 2 H), 7- 7.55 (d, J = 8.04 Hz, 1H), 7.49 (d, J = 1.56 Hz, 1 H),7.19 (dd, azabicyclo[2.2.1]heptan- J = 8.04, 1.69 Hz, 1 H), 6.22 (br d,J = 4.67 Hz, 1 H), 4.78 (dt, 2-yl)-4-(1-methyl-1H- J = 12.23, 6.02 Hz, 1H), 4.45-4.53 (m, 2 H), 4.11 (t, J = 4.93 Hz, pyrazol-4-yl)-3-(2- 1 H),3.97 (s, 3 H), 2.55 (ddd, J = 4.93, 3.11, 1.43 Hz, 1 H), 2.08propanyloxy)benzamide (dt, J = 7.69, 4.33 Hz, 1 H), 1.88-1.98 (m, 2 H),1.55-1.77 (m, 2 H), 1.43 (d, J = 6.10 Hz, 6 H), 1.18 (dd, J = 12.98,4.02 Hz, 1 H) 9-6 N-((1R,2R,4S)-7-cyano- ¹H NMR (500 MHz, DMSO-d₆) δ8.51 (d, J = 5.71 Hz, 1H), 8.20 7- (s, 1H), 7.97 (d, J = 0.65 Hz, 1H),7.70 (d, J = 8.04 Hz, 1H), 7.50 azabicyclo[2.2.1]heptan- (d, J = 7.99Hz, 1H), 7.48 (s, 1H), 4.24-4.34 (m, 2H), 4.17 (t, 2-yl)-3-methoxy-4-(1-J = 4.74 Hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 2.17-2.26 (m, 1H),methyl-1H-pyrazol-4- 1.78-1.90 (m, 2H), 1.64-1.73 (m, 2H), 1.57 (dd, J =4.61, 12.78 yl)benzamide Hz, 1H) 9-7 N-((1R,2R,4S)-7-cyano- 406.2 ¹H NMR(500 MHz, DMSO-d₆) δ 8.68 (d, J = 5.84 Hz, 1H), 7- 8.20 (s, 1H),7.85-7.98 (m, 4H), 4.24-4.33 (m, 2H), 4.17 (t, azabicyclo[2.2.1]heptan-J = 4.74 Hz, 1H), 3.88-3.93 (m, 3H), 2.18-2.26 (m, 1H), 1.79-1.892-yl)-4-(1-methyl-1H- (m, 2H), 1.64-1.72 (m, 2H), 1.57 (dd, J = 4.67,12.85 Hz, 1H) pyrazol-4-yl)-3- (trifluoromethoxy)benzamide 9-8N-((1R,2R,4S)-7-cyano- 390.2 ¹H NMR (500 MHz, DMSO-d₆) δ 8.79 (d, J =5.84 Hz, 1H), 8.24 7- (d, J = 1.69 Hz, 1H), 8.15 (dd, J = 1.69, 8.04 Hz,1H), 7.98 (s, 1H), azabicyclo[2.2.1]heptan- 7.67 (d, J = 8.11 Hz, 1H),7.64 (s, 1H), 4.25-4.34 (m, 2H), 4.18 (t, 2-yl)-4-(1-methyl-1H- J = 4.80Hz, 1H), 3.91 (s, 3H), 2.20-2.27 (m, 1H), 1.79-1.91 (m, pyrazol-4-yl)-3-2H), 1.64-1.73 (m, 2H), 1.57 (dd, J = 4.67, 12.85 Hz, 1H)(trifluoromethyl)benzamide 9-9 N-((1R,2R,4S)-7-cyano- 427 ¹H NMR (600MHz, DMSO-d₆) δ 13.90 (br s, 1H), 8.75 (d, 7- J = 5.99 Hz, 1H), 8.56 (d,J = 8.67 Hz, 1H), 8.46 (d, J = 8.02 Hz, azabicyclo[2.2.1]heptan- 1H),8.21 (t, J = 7.86 Hz, 1H), 8.13 (s, 1H), 7.90 (d, J = 7.63 Hz,2-yl)-3-(6- 1H), 7.77 (dd, J = 1.32, 8.56 Hz, 1H), 4.31-4.41 (m, 1H),4.28 (t, (trifluoromethyl)-2- J = 4.44 Hz, 1H), 4.19 (t, J = 4.87 Hz,1H), 2.20-2.28 (m, 1H), pyridinyl)-1H-indazole- 1.88-4.99 (m, 1H),1.79-4.88 (m, 1H), 1.66-1.75 (m, 2H), 1.60 6-carboxamide (dd, J = 4.67,12.69 Hz, 1H) 10-1 Racemic, endo 2-((3- 377 bromobenzyl)(methyl)amino)-N-(7-cyano-7- azabicyclo[2.2.1]heptan- 2-yl)acetamide 11-1 Racemic, endo2-(4- 388 chloro-2- cyclohexylphenoxy)-N- (7-cyano-7-azabicyclo[2.2.1]heptan- 2-yl)acetamide 11-2 N~2~-benzyl-N~2~-(3- 453.2,1H NMR (600 MHz, DMSO-d6) Shift 7.51-7.56 (m, 1H), 7.17- bromobenzyl)-N-455.2 7.34 (m, 9H), 4.03-4.12 (m, 2H), 3.96-4.03 (m, 1H), 3.66 (d,((1R,2R,4S)-7-cyano-7- J = 6.07 Hz, 3H), 3.63 (d, J = 7.79 Hz, 1H),2.97-3.06 (m, 2H), azobicyclo[2.2.1]heptan- 2.04-2.18 (m, 1H), 1.68-1.85(m, 1H), 1.48-1.66 (m, 3H), 1.18 2-yl)glycinamide (dd, J = 4.59, 12.77Hz, 1H) 11-3 N~2~-benzyl-N~2~-(3- 409.2 1H NMR (600 MHz, DMSO-d6) Shift7.91 (d, J = 6.23 Hz, 1H), chlorobenzyl)-N- 7.31-7.38 (m, 9H), 4.06-4.11(m, 2H), 4.01-4.05 (m, 1H), 3.71 ((1R,2R,4S)-7-cyano-7- (d, J = 3.35 Hz,4H), 3.06 (s, 2H), 2.08-2.15 (m, 1H), 1.72-1.81 azabicyclo[2.2.1]heptan-(m, 1H), 1.64-1.70 (m, 1H), 1.58-1.64 (m, 1H), 1.52-1.58 (m,2-yl)glycinamide 1H), 1.22 (dd, J = 4.63, 12.73 Hz, 1H) 11-4N-((1R,2R,4S)-7-cyano- 400.2 1H NMR (600 MHz, DMSO-d6) Shift 8.76 (s,1H), 8.67 (br d, 7- J = 6.07 Hz, 1H), 4.15-4.24 (m, 5H), 3.12 (br s,2H), 2.94 (br s, azabicyclo[2.2.1]heptan- 2H), 2.23-2.32 (m, 1H), 2.01(ddd, J = 4.40, 8.76, 12.77 Hz, 1H), 2-yl)-2-(5,6,7,8- 1.87-1.97 (m,5H), 1.65-1.81 (m, 2H), 1.38 (dd, J = 4.36, 12.69tetrahydro[1]benzothieno Hz, 1H) [2,3-d]pyrimidin-4-ylsulfanyl)acetamide 11-5 N~2~-(3-bromobenzyl)- 419.2, 1H NMR (600 MHz,DMSO-d6) Shift 7.84 (br d, J = 6.15 Hz, N-((1R,2R,4S)-7-cyano- 421.21H), 7.50 (s, 1H), 7.40 (d, J = 7.79 Hz, 1H), 7.27-7.30 (m, 1H), 7-7.22-7.27 (m, 1H), 4.05-4.10 (m, 2H), 4.00-4.05 (m, 1H), 3.61-azobicyclo[2.2.1]heptan- 3.70 (m, 2H), 2.99-3.07 (m, 2H), 2.17-2.26 (m,2H), 2.09-2.17 2-yl)-N~2~-(2- (m, 1H), 1.66-1.79 (m, 3H), 1.56-1.64 (m,1H), 1.48-1.55 (m, methylpropyl)glycinamide 1H), 1.10-1.21 (m, 1H), 0.80(dd, J = 3.00, 6.58 Hz, 6H) 11-6 N~2~-(3-chlorobenzyl)- 439.2 1H NMR(600 MHz, DMSO-d6) Shift 7.84 (d, J = 6.31 Hz, 1H),N-((1R,2R,4S)-7-cyano- 7.40 (s, 1H), 7.29-7.33 (m, 1H) 7.25-7.29 (m,2H), 7.22 (d, 7- J = 8.56 Hz, 2H), 6.86 (d, J = 8.64 Hz, 2H), 4.02-4.10(m, 2H), azabicyclo[2.2.1]heptan- 3.96-4.02 (m, 1H), 3.69 (s, 3H), 3.59(s, 2H), 2.94-3.03 (m, 2H), 2-yl)-N~2~-(4- 2.04-2.13 (m, 1H), 1.68-1.81(m, 1H), 1.60-1.66 (m, 1H), 1.55- methoxybenzyl)glycinamide 1.60 (m,1H), 1.49-1.55 (m, 1H), 1.19 (dd, J = 4.63, 12.73 Hz, 1H) 11-7N-((1R,2R,4S)-7-cyano- 379.2 1H NMR (600 MHz, DMSO-d6) Shift 8.08 (br d,J = 6.68 Hz, 7- 1H), 7.40 (d, J = 2.10 Hz, 1H), 7.18 (d, J = 2.02 Hz,1H), 4.03-4.12 azabicyclo[2.2.1]heptan- (m, 3H), 3.57-3.68 (m, 2H),3.06-3.17 (m, 3H), 2.66-2.78 (m, 2-yl)-2-(5,7-dichloro- 4H), 2.04-2.13(m, 1H), 1.68-1.79 (m, 2H), 1.56-1.65 (m, 2H), 3,4-dihydro-2(1H)- 1.35(dd, J = 4.20, 12.69 Hz, 1H) isoquinolinyl)acetamide 11-8 Racemic, endoN-(7- 382 cyano-7- azabicyclo[2.2.1]heptan- 2-yl)-2-(2,4-dichloro-5-ethyl-3- methylphenoxy)acetamide 11-9 Racemic, endo 2-((5- 378.9chlorobenzo[d]thiazol-2- yl)thio)-N-(7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)acetamide 12-1 Racemic, endo 2-(4-((4- 376chlorophenyl)thio)piperidine 1-carbonyl)-7- azabicyclo[2.2.1]heptane-7-carbonitrile 13-1 Racemic, endo N-(7- ¹H NMR (600 MHz, DMSO-d₆) δ 8.97(d, J = 4.83 Hz, 1H), 8.41 cyano-7- (d, J = 6.86 Hz, 1H), 8.30 (d, J =9.03 Hz, 1H), 7.80 (s, 1H), 7.81 azabicyclo[2.2.1]heptan- (d, J = 7.04Hz, 1H), 7.39 (d, J = 4.90 Hz, 1H), 4.25-4.32 (m, 3H),2-yl)-1-(4-methyl-2- 4.14-4.25 (m, 2H), 3.23-3.30 (m, 2H), 2.16-2.23 (m,1H), 1.77- pyrimidinyl)-2,3- 1.91 (m, 2H), 1.63-1.73 (m, 2H), 1.53-1.60(m, 1H) dihydro-1H-indole-5- carboxamide 13-2 Racemic, endo N-(7- 351.2¹H NMR (600 MHz, DMSO-d₆) δ 8.42 (d, J = 5.99 Hz, 1H), 8.04 cyano-7- (brs, 1H), 7.75 (s, 1H), 7.70 (br d, J = 8.41 Hz, 1H), 4.34 (br s,azabicyclo[2.2.1]heptan- 2H), 4.19-4.31 (m, 2H), 4.15 (t, J = 4.75 Hz,1H), 3.22 (br t, 2-yl)-1- J = 8.29 Hz, 2H), 2.15-2.21 (m, 1H), 1.97 (brs, 1H), 1.76-1.88 (cyclopropylcarbonyl)- (m, 2H), 1.62-1.72 (m, 2H),1.55 (dd, J = 4.75, 12.69 Hz, 1H), 2,3-dihydro-1H-indole- 0.83-0.95 (m,4H) 5-carboxamide 13-3 6-chloro-N-((1R,2R,4S)- 407.0 ¹H NMR (500 MHz,CHLOROFORM-d) δ ppm 8.84-8.99 (m, 7-cyano-7- 1H), 8.09-8.21 (m, 1H),8.04 (s, 1 H), 7.79 (br d, J = 7.79 Hz, 1 azabicyclo[2.2.1]heptan- H),7.72 (br t, J = 7.66 Hz, 1H), 7.05 (br d, J = 7.14 Hz, 1 H),2-yl)-1-(6-methyl-2- 6.69-6.85 (m, 1 H), 4.51-4.64 (m, 1 H), 4.48 (br s,1 H), 4.10 (br s, pyridinyl)-1H-indazole- 1 H), 2.65 (br s, 3 H), 2.53(br s, 1 H), 2.02-2.18 (m, 2 H), 5-carboxamide 1.64-1.76 (m, 2 H),1.19-1.29 (m, 1 H) 13-4 N-((1R,2R,4S)-7-cyano- 373.0 ¹H NMR (500 MHz,CHLOROFORM-d) δ ppm 8.92 (d, J = 8.82 7- Hz, 1 H), 8.24 (s, 1 H), 8.22(s, 1H), 7.80-7.93 (m, 2 H), 7.74 azabicyclo[2.2.1]heptan- (t, J = 7.85Hz, 1 H) 7.06 (d, J = 7.40 Hz, 1 H) 6.34 (br d, J = 5.062-yl)-1-(6-methyl-2- Hz, 1 H), 4.47-4.60 (m, 2 H), 4.12 (t, J = 4.93 Hz,1 H), 2.66 (s, pyridinyl)-1H-indazole- 3 H), 2.04-2.18 (m, 1 H),1.91-2.04 (m, 2 H), 1.55-1.65 (m, 2 5-carboxamide H), 1.18-1.26 (m, 1 H)13-5 N-((1R,2R,4S)-7-cyano- 391.0 ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm8.65-8.62 (m, 7- 1 H), 8.53 (d, J = 7.40 Hz, 1 H), 8.25 (s, 1 H), 7.84(br d, J = 8.04 azabicyclo[2.2.1]heptan- Hz, 1 H), 7.74 (br t, J = 7.66Hz, 1 H), 7.07 (br d, J = 7.27 Hz, 1 2-yl)-6-fluoro-1-(6- H), 6.82-6.99(m, 1 H), 4.47-4.60 (m, 2 H), 4.12 (t, J = 4.93 Hz,methyl-2-pyridinyl)-1H- 1 H), 2.66 (s, 3 H), 2.04-2.18 (m, 1 H),1.91-2.04 (m, 2 H), indazole-5-carboxamide 1.55-1.65 (m, 2 H), 1.20 (dd,J = 12.85, 3.89 Hz, 1 H) 13-6 Racemic, endo N-(7- 417.2 ¹H NMR (500 MHz,DMSO-d₆) δ 8.41 (d, J = 6.23 Hz, 1H), 8.35 cyano-7- (d, J = 5.06 Hz,1H), 8.12 (d, J = 8.69 Hz, 1H), 7.42 (s, 1H), 7.39azabicyclo[2.2.1]heptan- (d, J = 8.28 Hz, 1H), 6.93 (d, J = 5.06 Hz,1H), 4.14-4.31 (m, 7H), 2-yl)-4-(4-cyclopropyl- 2.19 (br s, 1H),2.02-2.08 (m, 1H), 1.77-1.88 (m, 2H), 1.63-1.72 2-pyrimidinyl)-3,4- (m,2H), 1.57 (dd, J = 4.67, 12.72 Hz, 1H), 1.00-1.06 (m, 4H)dihydro-2H-1,4- benzoxazine-7- carboxamide 13-7 2-((4-chloro-1- 356.2 ¹HNMR (500 MHz, DMSO-d₆) δ 8.52 (br d, J = 5.58 Hz, 1H),naphthalenyl)oxy)-N- 8.34 (d, J = 8.17 Hz, 1H), 8.13 (d, J = 8.43 Hz,1H), 7.74 (dt, ((1R,2R,4S)-7-cyano-7- J = 1.23, 7.62 Hz, 1H), 7.64-7.68(m, 1H), 7.60 (d, J = 8.30 Hz, azabicyclo[2.2.1]heptan- 1H), 6.89 (d, J= 8.43 Hz, 1H), 4.77 (s, 2H), 4.10-4.23 (m, 3H), 2-yl)acetamide2.14-2.26 (m, 1H), 1.76-1.91 (m, 2H), 1.56-1.72 (m, 2H), 1.34- 1.41 (m,1H) 13-8 2-((4-chloro-1- 356.2 ¹H NMR (500 MHz, DMSO-d₆) δ 8.52 (br d, J= 5.45 Hz, 1H), naphthalenyl)oxy)-N- 8.34 (d, J = 8.30 Hz, 1H), 8.13 (d,J = 8.30 Hz, 1H), 7.73 (t, J = 7.73 ((1R,2R,4S)-7-cyano-7- Hz, 1H), 7.66(t, J = 7.74 Hz, 1H), 7.60 (d, J = 8.18 Hz, 1H), 6.89azabicyclo[2.2.1]heptan- (d, J = 8.30 Hz, 1H), 4.73-4.80 (m, 2H),4.12-4.21 (m, 3H), 2.15- 2-yl)acetamide (peak 2 2.23 (m, 1H), 1.76-1.90(m, 2H), 1.57-1.70 (m, 2H), 1.38 (dd, derived) J = 4.02, 12.85 Hz, 1H)13-9 Racemic, endo 2-methyl- 383.3 ¹H NMR (500 MHz, DMSO-d₆) δ 8.38 (d,J = 5.97 Hz, 1H), 7.72 2-propanyl 5-((7-cyano- (d, J = 7.07 Hz, 1H),7.71 (s, 1H), 4.19-4.30 (m, 2H), 4.15 (t, 7- J = 4.80 Hz, 1H), 3.95 (t,J = 8.76 Hz, 2H), 3.10 (t, J = 8.76 Hz, azabicyclo[2.2.1]heptan- 2H),2.14-2.22 (m, 1H), 1.76-1.88 (m, 2H), 1.61-1.72 (m, 2H),2-yl)carbamoyl)-2,3- 1.47-1.57 (m, 10H) dihydro-1H-indole-1- carboxylate13-10 Racemic, endo N-(7- 374.2 ¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (d, J =5.08 Hz, 1H), 8.69- cyano-7,- 8.75 (m, 2H), 8.61 (d, J = 0.83 Hz, 1H),8.45 (dd, J = 0.67, 1.61 azabicyclo[2.2.1]heptan- Hz, 1H), 8.07 (dd, J =1.66, 8.91 Hz, 1H), 7.37 (d, J = 5.08 Hz, 2-yl)-1-(4-methyl-2- 1H),4.31-4.40 (m, 1H), 4.28 (t, J = 4.46 Hz, 1H), 4.18 (t, J = 4.82pyrimidinyl)-1H- Hz, 1H), 2.62 (s, 3H), 2.20-2.28 (m, 1H), 1.79-1.99 (m,2H), indazole-5-carboxamide 1.65-1.76 (m, 2H), 1.59 (dd, J = 4.66, 12.75Hz, 1H) 13-11 Racemic, endo N-(7- 374 ¹H NMR (500 MHz, DMSO-d₆) δ 9.21(s, 1H), 8.82 (d, J = 5.06 cyano-7- Hz, 1H), 8.69 (d, J = 6.10 Hz, 1H),8.63 (d, J = 8.69 Hz, 1H), 8.39 azabicyclo[2.2.1]heptan- (d, J = 1.17Hz, 1H), 7.97 (dd, J = 1.69, 8.69 Hz, 1H), 7.44 (d, 2-yl)-1-(4-methyl-2-J = 5.06 Hz, 1H), 4.32-4.38 (m, 1H), 4.25-4.29 (m, 1H), 4.18 (t,pyrimidinyl)-1H- J = 4.87 Hz, 1H), 2.63 (s, 3H), 2.19-2.26 (m, 1H),1.80-1.96 (m, benzimidazole-5- 2H), 1.67-1.76 (m, 2H), 1.62 (dd, J =4.80, 12.72 Hz, 1H) carboxamide 13-12 Racemic, endo N-(7- 399 ¹H NMR(500 MHz, DMSO-d₆) δ 8.75 (d, J = 8.78 Hz, 1H), 8.72 cyano-7- (d, J =6.29 Hz, 1H), 8.59 (s, 1H), 8.44 (s, 1H), 8.41 (d, J = 5.69azabicyclo[2.2.1]heptan- Hz, 1H), 8.03 (dd, J = 1.56, 8.95 Hz, 1H), 7.76(s, 1H), 7.05 (d, 2-yl)-1-(4-cyclopropyl- J = 5.32 Hz, 1H), 4.34 (br dd,J = 5.19, 10.64 Hz, 1H), 4.27 (t, 2-pyridinyl)-1H- J = 4.54 Hz, 1H),4.18 (t, J = 4.80 Hz, 1H), 2.19-2.27 (m, 1H), indazole-5-carboxamide2.09-2.16 (m, 1H), 1.87-1.96 (m, 1H), 1.79-1.87 (m, 1H), 1.65- 1.75 (m,2H), 1.59 (dd, J = 4.74, 12.65 Hz, 1H), 1.11-1.21 (m, 2H) 0.88-0.94 (m,2H) 13-13 Racemic, endo N-(7- 399 ¹H NMR (500 MHz, DMSO-d₆) δ 8.68 (d, J= 6.39 Hz, 1H), 8.65 cyano-7- (d, J = 8.70 Hz, 1H), 8.58 (d, J = 0.78Hz, 1H), 8.44 (s, 1H), 8.09 azabicyclo[2.2.1]heptan- (dd, J = 1.69, 8.95Hz, 1H), 7.86 (t, J = 7.77 Hz, 1H), 7.76 (dd, 2-yl)-1-(6-cyclopropyl- J= 0.78, 8.17 Hz, 1H), 7.30 (dd, J = 0.71, 7.46 Hz, 1H), 4.32-4.392-pyridinyl)-1H- (m, 1H), 4.27 (t, J = 4.54 Hz, 1H), 4.19 (t, J = 4.87Hz, 1H), 2.20- indazole-5-carboxamide 2.29 (m, 2H), 1.89-1.99 (m, 1H),1.79-1.88 (m, 1H), 1.65-1.75 (m, 2H), 1.60 (dd, J = 4.74, 12.65 Hz, 1H),1.08-1.14 (m, 4H) 13-14 N-((1R,2R,4S)-7-cyano- 398.9 ¹H NMR (500 MHz,DMSO-d₆) δ 8.62-8.69 (m, 2H), 8.57 (d, 7- J = 0.65 Hz, 1H), 8.44 (d, J =1.04 Hz, 1H), 8.09 (dd, J = 1.69, 8.95 azabicyclo[2.2.1]heptan- Hz, 1H),7.86 (t, J = 7.72 Hz, 1H), 7.76 (dd, J = 0.71, 8.11 Hz,2-yl)-1-(6-cyclopropyl- 1H), 7.30 (d, J = 7.51 Hz, 1H), 4.32-4.39 (m,1H), 4.27 (t, J = 4.61 2-pyridinyl)-1H- Hz, 1H), 4.18 (t, J = 4.93 Hz,1H), 2.20-2.29 (m, 2H), 1.90-1.97 indazole-5-carboxamide (m, 1H),1.79-1.88 (m, 1H), 1.65-1.76 (m, 2H), 1.60 (dd, J = 4.74, 12.78 Hz, 1H),1.08-1.14 (m, 4H) 13-15 3-(4-chloro-3- 372 ¹H NMR (600 MHz, DMSO-d₆) δ8.11 (br d, J = 6.38 Hz, 1H), (trifluoromethyl)phenyl)- 7.67 (s, 1H),7.63 (d, J = 8.32 Hz, 1H), 7.52 (dd, J = 1.71, 8.25 Hz,N-((1R,2R,4S)-7-cyano- 1H), 3.97-4.10 (m, 3H), 2.87-2.94 (m, 2H),2.38-2.48 (m, 2H), 7- 2.08-2.14 (m, 1H), 1.71-1.78 (m, 1H), 1.44-1.56(m, 3H), 1.09- azabicyclo[2.2.1]heptan- 1.16 (m, 1H) 2-yl)propanamide13-16 N-((1R,2R,4S)-7-cyano- 387.2 ¹H NMR (600 MHz, DMSO-d₆) δ 8.86 (d,J = 8.88 Hz, 1H), 8.69 7- (d, J = 6.07 Hz, 1H), 8.59 (s, 1H), 8.45 (s,1H), 8.08 (dd, J = 1.63, azobicyclo[2.2.1]heptan- 8.88 Hz, 1H), 7.93 (t,J = 7.82 Hz, 1H), 7.84 (d, J = 8.10 Hz, 1H), 2-yl)-1-(6-ethyl-2- 7.23(d, J = 7.47 Hz, 1H), 4.32-4.39 (m, 1H), 4.28 (t, J = 4.55 Hz,pyridinyl)-1H-indazole- 1H), 4.19 (t, J = 4.90 Hz, 1H), 2.92 (q, J =7.55 Hz, 2H), 2.21-2.27 5-carboxamide (m, 1H), 1.89-1.98 (m, 1H),1.80-1.88 (m, 1H), 1.67-1.76 (m, 2H), 1.60 (dd, J = 4.71, 12.73 Hz, 1H),1.38 (t, J = 7.55 Hz, 3H) 13-17 N-((1R,2R,4S)-7-cyano- 374.2 ¹H NMR (600MHz, DMSO-d₆) δ 9.15 (d, J = 8.64 Hz, 1H.), 9.02 7- (d, J = 6.46 Hz,1H), 8.76 (d, J = 4.98 Hz, 1H), 8.69 (d, J = 3.74 Hz,azobicyclo[2.2.1]heptan- 1H), 8.05 (d, J = 8.64 Hz, 1H), 7.34 (d, J =5.06 Hz, 1H), 7.02 (d, 2-yl)-1-(4-methyl-2- J = 3.74 Hz, 1H), 4.31-4.39(m, 1H), 4.28 (t, J = 4.71 Hz, 1H), 4.18 pyrimidinyl)-1H- (t, J = 4.87Hz, 1H), 2.61 (s, 3H), 2.18-2.24 (m, 1H), 1.77-1.92pyrrolo[3,2-b]pyridine- (m, 4H), 1.65-1.74 (m, 1H) 5-carboxamide 13-18N-((1R,2R,4S)-7-cyano- 391.2 ¹H NMR (600 MHz, DMSO-d₆) δ 8.75 (d, J =5.06 Hz, 1H), 8.59- 7- 8.66 (m, 2H), 8.37 (d, J = 3.66 Hz, 1H), 7.52(dd, J = 7.08, 8.56 azabicyclo[2.2.1]heptan- Hz, 1H), 7.32 (d, J = 5.06Hz, 1H), 6.95 (d, J = 3.74 Hz, 1H), 4.25- 2-yl)-4-fluoro-1-(4- 4.37 (m,2H), 4.17 (t, J = 4.90 Hz, 1H), 2.60 (s, 3H), 2.20-2.27methyl-2-pyrimidinyl)- (m, 1H), 1.98 (ddd, J = 4.28, 8.89, 12.75 Hz,1H), 1.77-1.88 (m, 1H-indole-5- 1H), 1.63-1.76 (m, 2H), 1.48 (dd, J =4.59, 12.77 Hz, 1H) carboxamide 13-19 N-((1R,2R,4S)-7-cyano- 363.2 ¹HNMR (600 MHz, DMSO-d₆) δ 8.53 (d, J = 5.99 Hz, 1H), 8.25 7- (d, J = 4.98Hz, 1H), 7.82-7.87 (m, 2H), 7.44-7.49 (m, 2H), 6.70azabicyclo[2.2.1]heptan- (d, J = 4.98 Hz, 1H), 4.22-4.34 (m, 2H), 4.16(t, J = 4.87 Hz, 1H), 2-yl)-4-(methyl(4- 3.50 (s, 3H), 2.29 (s, 3H),2.17-2.26 (m, 1H), 1.78-1.91 (m, 2H), methyl-2- 1.64-1.76 (m, 2H), 1.57(dd, J = 4.67, 12.69 Hz, 1H) pyrimidinyl)amino)benzamide 13-20N-((1R,2R,4S)-7-cyano- 387.2 ¹H NMR (600 MHz, DMSO-d₆) δ 8.78 (d, J =5.06 Hz, 1H), 8.48- 7- 8.56 (m, 1H), 8.05 (s, 1H), 7.85 (d, J = 3.43 Hz,1H), 7.58 (s, 1H), azabicyclo[2.2.1]heptan- 7.40 (d, J = 5.06 Hz, 1H),6.84 (d, J = 3.50 Hz, 1H), 4.33 (br dd, 2-yl)-4-methyl-1-(4- J = 4.83,11.13 Hz, 1H), 4.24-4.28 (m, 1H), 4.15-4.19 (m, 1H),methyl-2-pyrimidinyl)- 2.55-2.58 (m, 3H), 2.30-2.34 (m, 3H), 2.16-2.27(m, 1H), 1.91 1H-indole-5- (dt, J = 3.78, 8.74 Hz, 1H), 1.78-1.86 (m,1H), 1.65-1.76 (m, 2H), carboxamide 1.57-1.64 (m, 1H) 14-1 Racemic, endoN-(7- 335.2 ¹H NMR (600 MHz, DMSO-d₆) δ 9.92 (s, 1H), 8.53 (d, J = 4.75cyano-7- Hz, 2H), 8.37 (d, J = 5.99 Hz, 1H), 7.83-7.89 (m, J = 8.88 Hz,2H), azobicyclo[2.2.1]heptan- 7.78-7.83 (m, J = 8.80 Hz, 2H), 6.91 (t, J= 4.79 Hz, 1H), 4.21- 2-yl)-4-(2- 4.30 (m, 2H), 4.15 (t, J = 4.87 Hz,1H), 2.15-2.23 (m, 1H), 1.77- pyrimidinylamino)benzamide 1.90 (m, 2H),1.63-1.73 (m, 2H), 1.55 (dd, J = 4.67, 12.69 Hz, 1H) 14-2N-((1R,2R,4S)-7-cyano- 376.2 ¹H NMR (500 MHz, DMSO-d₆) δ 11.66 (s, 1H),8.60 (d, J = 6.23 7- Hz, 1H), 7.73 (d, J = 8.30 Hz, 1H), 7.38 (s, 1H),7.27 (d, J = 1.43 azobicyclo[2.2.1]heptan- Hz, 1H), 7.04 (dd, J = 1.36,8.24 Hz, 1H), 4.30-4.37 (m, 1H), 4.26 2-yl)-6-(3,5-dimethyl- (t, J =4.41 Hz, 1H), 4.19 (t, J = 4.80 Hz, 1H), 2.41 (s, 3H), 2.21-1,2-oxazol-4-yl)-1H- 2.28 (m, 4H), 1.80-1.93 (m, 2H), 1.66-1.75 (m, 2H),1.55 (dd, indole-2-carboxamide J = 4.67, 12.72 Hz, 1H) 14-3N-((1R,2R,4S)-7-cyano- 401.2 ¹H NMR (500 MHz, DMSO-d₆) δ 8.39 (d, J =5.33 Hz, 1H), 8.36 7- (d, J = 6.34 Hz, 1H), 8.24 (d, J = 8.43 Hz, 1H),7.72-7.77 (m, 2H), azobicyclo[2.2.1]heptan- 6.92 (d, J = 5.06 Hz, 1H),4.25-4.32 (m, 1H), 4.14-4.24 (m, 4H), 2-yl)-1-(4-cyclopropyl- 3.15-3.30(m, 2H), 2.15-2.23 (m, 1H), 2.05-2.11 (m, 1H), 1.77- 2-pyrimidinyl)-2,3-1.90 (m, 2H), 1.62-1.73 (m, 2H), 1.57 (dd, J = 4.80, 12.72 Hz,dihydro-1H-indole-5- 1H), 1.06-1.15 (m, 4H) carboxamide 14-4N-((1R,2R,4S)-7-cyano- 401.2 ¹H NMR (500 MHz, DMSO-d₆) δ 8.39 (d, J =5.31 Hz, 1H), 8.36 7- (d, J = 6.33 Hz, 1H), 8.24 (J = 8.43 Hz, 1H),7.72-7.77 (m, 2H), azabicyclo[2.2.1]heptan- 6.92 (d, J = 5.06 Hz, 1H),4.14-4.31 (m, 5H), 3.18 (t, J = 8.82 Hz, 2-yl)-1-(4-cyclopropyl- 2H),2.15-2.23 (m, 1H), 2.05-2.11 (m, 1H), 1.77-1.90 (m, 2H),2-pyrimidinyl)-2,3- 1.62-1.73 (m, 2H), 1.57 (dd, J = 4.74, 12.65 Hz,1H), 1.06-1.15 dihydro-1H-indole-5- (m, 4H) carboxamide 14-5N-((1R,2R,4S)-7-cyano- 322.2 ¹H NMR (500 MHz, DMSO-d₆) δ 8.51 (d, J =5.84 Hz, 1H), 8.25 7- (s, 1H), 7.95 (s, 1H), 7.84-7.87 (m, J = 8.43 Hz,2H), 7.65-7.69 azabicyclo[2.2.1]heptan- (m, J = 8.43 Hz, 2H), 4.26-4.33(m, 1H), 4.22-4.26 (m, 1H), 4.16 2-yl)-4-(1-methyl-1H- (t, J = 4.74 Hz,1H), 3.87 (s, 3H), 3.24-3.30 (m, 1H), 2.16-2.24 pyrazol-4-yl)benzamide(m, 1H), 1.78-1.90 (m, 2H), 1.63-1.72 (m, 2H), 1.57 (dd, J = 4.74, 12.65Hz, 1H) 15-1 6-chloro-N-((1R,2R,4S)- 409 ¹H NMR (600 MHz, DMSO-d₆) δ8.64 (br d, J = 5.60 Hz, 1H), 7-cyano-7- 8.50 (d, J = 4.98 Hz, 1H), 8.41(s, 1H), 7.31 (s, 1H), 6.88 (d, azabicyclo[2.2.1]heptan- J = 4.98 Hz,1H), 4.21-4.26 (m, 4H), 4.09-4.19 (m, 1H), 3.20 (br 2-yl)-1-(4-methyl-2-s, 1H), 3.16 (t, J = 8.68 Hz, 2H), 2.44 (s, 3H), 2.15-2.24 (m, 1H),pyrimidinyl)-2,3- 1.99 (ddd, J = 4.17, 8.99, 12.85 Hz, 1H), 1.75-1.86(m, 1H), 1.66- dihydro-1H-indole-5- 1.74 (m, 1H), 1.56-1.65 (m, 1H),1.40 (dd, J = 4.01, 12.81 Hz, carboxamide 1H) 16-1 5-(3-chlorophenyl)-N-373.0 1H NMR (500 MHz, CHLOROFORM-d) Shift 7.45-7.46 (m,((1R,2R,4S)-7-cyano-7- 1H), 7.39-7.42 (m, 2H), 7.33-7:37 (m, 1H),7.25-7.28 (m, 1H), azabicyclo[2.2.1]heptan- 4.48-4.55 (m, 1H), 4.42-4.45(m, 1H), 4.12-4.16 (m, 1H), 2.51- 2-yl)-4-methyl-1,3- 2.60 (m, 4H),2.07-2.16 (m, 1H), 1.93-2.05 (m, 2H), 1.68-1.74 thiazole-2-carboxamide(m, 1H), 1.24-1.34 (m, 1H) 16-2 5-(3-chlorophenyl)-N- 359.0 1H NMR (500MHz, CHLOROFORM-d) Shift 8.00-8.02 (m, ((1R,2R,4S)-7-cyano-7- 1H), 7.61(td, J = 1.17, 1.82 Hz, 1H), 7.45-7.53 (m, 1H), 7.38-azobicyclo[2.2.1]heptan- 7.43 (m, 2H), 7.23-7.28 (m, 1H), 4.51-4.57 (m,1H), 4.41-4.45 2-yl)-1,3-thiazole-2- (m, 1H), 4.14 (t, J = 5.13 Hz, 1H),2.57 (dddd, J = 2.98, 5.16, carboxamide 11.13, 13.04 Hz, 1H), 2.07-2.16(m, 1H), 1.94-2.02 (m, 2H), 1.66-1.72 (m, 1H), 1.24-1.31 (m, 1H) 1-652-chloro-N-((1R,2R,4S)- 359.0 1H NMR (DMSO-d6) δ: 10.49 (s, 1H). 8.68(br d, J = 5.8 Hz, 7-cyano-7- 1H), 7.85 (d, J = 1.9 HZ, 1H), 7.49 (dd, J= 8.4, 1.9 Hz, 1H), 7.39 azabicyclo[2.2.1]heptan- (d, J = 8.4 Hz, 1H),4.20-4.26 (m, 2H), 4.14 (t, J = 4.9 Hz, 1H), 2-yl)-4- 2.15-2.24 (m, 1H),1.97 (ddd, J = 12.9, 9.0, 4.2 Hz, 1H), 1.79-1.83 ((cyclopropylcar- (m,1H), 1.73-1.79 (m, 1H), 1.65-1.73 (m, 1H), 1.56-1.63 (m,bonyl)amino)benzamide 1H), 1.38 (dd, J = 12.8, 4.0 Hz, 1H), 0.80-0.86(m, 4H) 1-66 2-chloro-N-((1R,2R,4S)- 390.1 1H NMR (DMSO-d6) δ: 8.89 (brd, J = 5.9 Hz, 1H), 8.46 (s, 1H), 7-cyano-7- 7.91-7.97 (m, 3H), 7.88(dd, J = 8.3, 2.1 Hz, 1H), 7.67 (d, J = 8.3 azabicyclo[2.2.1]heptan- Hz,1H), 7.57 (t, J = 7.7 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 4.26-2-yl)-4-(1H-indazol-1- 4.31 (m, 2H), 4.12-4.21 (m, 1H), 2.17-2.32 (m,1H), 2.02 (ddd, yl)benzamide J = 12.9, 9.0, 4.0 Hz, 1H), 1.78-1.87 (m,1H), 1.69-1.78 (m, 1H), 1.57-1.66 (m, 1H), 1.40 (dd, J = 12.7, 4.2 Hz,1H) 1-68-2 (3S)-6-chloro-N- 369.1 1H NMR (DMSO-d6) δ: 10.8:3 (s, 1H),8.15 (br d, J = 6.0 Hz, (1R,2R,4S)-7-cyano-7- 1H), 7.30 (d, J = 1.8 Hz,1H), 7.17 (d, J = 8.5 Hz, 1H), 6.90 (dd, azabicyclo[2.2.1]heptan- J =8.5, 2.0 Hz, 1H), 4.02-4.09 (m, 3H), 2.64-2.74 (m, 3H), 2.57-2-yl)-2,3,4,9-tetrahydro- 2.63 (m, 1H), 2.53 (dt, J = 9.4, 2.3 Hz, 1H),2.05-2.18 (m, 1H), 1H-carbazole-3- 1.91-2.03 (m, 1H), 1.69-4.84 (m, 3H),1.56-1.64 (m, 1H), 1.49- carboxamide 1.56 (m, 1H), 1.22 (dd, J = 12.7,4.5 Hz, 1H) 1-69 (4R)-7-chloro-N- 346.0 1H NMR (DMSO-d6) δ: 8.15 (br t,J = 6.1 Hz, 1H), 7.31 (dd, ((1R,2R,4S)-7-cyano-7- J = 17.3, 2.6 Hz, 1H),7.17 (dt, J = 8.4, 1.9 Hz, 1H), 6.94 (d, J = 8.5azabicyclo[2.2.1]heptan- Hz, 1H), 4.30-4.39 (m, 1H), 4.05-4.15 (m, 3H),3.58-3.66 (m, 2-yl)-2,3,4,5-tetrahydro- 1H), 2.90-2.99 (m, 1H), 2.75 (brd, J = 14.4 Hz, 1H), 2.42-2.48 1-benzoxepine-4- (m, 1H), 2.13-2.21 (m,1H), 1.93-2.09 (m, 2H), 1.75-4.90 (m, carboxamide 2H), 1.52-1.69 (m,2H), 1.24 (dt, J = 12.7, 4.4 Hz, 1H) 1-70 5-chloro-N-((1R,2R,4S)- 421.21H NMR (DMSO-d6) δ: 8.91 (d, J = 6.0 Hz, 1H), 8.69 (s, 1H), 7-cyano-7-7.90-7.93 (m, 2H), 7.79 (t, J = 7.8 Hz, 1H), 7.26 (d, J = 7.7 Hz,azabicyclo[2.2.1]heptan- 1H), 4.28-4.34 (m, 2H), 4.13-4.22 (m, 4H),2.61-2.62 (m, 3H), 2-yl)-1-methyl-3-(6- 2.25 (br d, J = 1.9 Hz, 1H),2.08 (ddd, J = 12.8, 9.0, 3.9 Hz, 1H), methyl-2-pyridinyl)-1H- 1.70-1.87(m, 2H), 1.58-1.65 (m, 1H), 1.41 (dd, J = 12.8, 4.0 Hz,indazole-6-carboxamide 1H) 1-71 N-((1R,2R,4S)-7-cyano- 427.2 1H NMR(DMSO-d6) δ: 8.62-8.73 (m, 2H), 8.24 (s, 1H), 7.94 7- (d, J = 7.8 Hz,1H), 7.79 (t, J = 7.7 Hz, 1H), 7.73 (dd, J = 8.4, 1.3azabicyclo[2.2.1]heptan- Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 4.46 (d, J =7.0 Hz, 2H), 4.27- 2-yl)-1- 4.38 (m, 2H), 4.20 (t, J = 5.0 Hz, 1H), 2.62(s, 3H), 2.21-2.32 (m, (cyclopropylmethyl)-3- 1H, 1.89-1.99 (m, 1H),1.80-1.89 (m, 1H), 1.66-1.76 (m, 2H), (6-methyl-2-pyridinyl)- 1.60 (dd,J = 12.7, 4.5 Hz, 1H), 1.35-1.44 (m, 1H), 0.51-0.57 (m, 1H-indazole-6-2H), 0.45-0.51 (m, 2H) carboxamide 1-72 N-((1R,2R,4S)-7-cyano- 429.0 1HNMR (DMSO-d6) δ: 8.68 (d, J = 7.8 Hz, 2H), 8.18 (s, 1H), 7- 7.93 (d, J =7.8 Hz, 1H), 7.78 (t, J = 7.7 Hz, 1H), 7.72 (dd, J = 8.6,azabicyclo[2.2.1]heptan- 1.2 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H),4.29-4.39 (m, 4H), 4.19 (t, 2-yl)-1-(2- J = 4.9 Hz, 1H), 2.62 (s, 3H),2.32-2.39 (m, 1H), 2.21-2.31 (m, methylpropyl)-3-(6- 1H), 1.88-1.96 (m,1H), 1.80-1.88 (m, 1H), 1.67-1.76 (m, 2H), methyl-2-pyridinyl)-1H- 1.60(dd, J = 12.8, 4.6 Hz, 1H), 0.91 (br d, J = 6.6 Hz, 3H), 0.91 (brindazole-6-carboxamide d, J = 6.6 Hz, 3H) 1-73 N-((1R,2R,4S)-7-cyano-482.8 1H NMR (DMSO-d6) δ: 8.66-8.73 (m, 2H), 8.21 (s, 1H), 7.94 7- (d, J= 7.9 Hz, 1H), 7.80 (t, J = 7.7 Hz, 1H), 7.73 (dd, J = 8.5, 1.3azabicyclo[2.2.1]heptan- Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 4.64 (t, J =7.0 Hz, 2H), 4.28- 2-yl)-3-(6-methyl-2- 4.37 (m, 2H), 4.20 (t, J = 4.9Hz, 1H), 2.62 (s, 3H), 2.34-2.43 (m, pyridinyl)-1-(4,4,4- 2H), 2.22-2.30(m, 1H), 2.12-2.21 (m, 2H), 1.89-1.97 (m, 1H), trifluorobutyl)-1H-1.80-1.88 (m, 1H), 1.67-1.75 (m, 2H), 1.60 (dd, J = 12.7, 4.6 Hz,indazole-6-carboxamide 1H) 1-74 N-((1R,2R,4S)-7-cyano- 415.0 1H NMR(DMSO-d6) δ: 8.64-8.72 (m, 2H), 8.19 (s, 1H), 7.93 7- (d, J = 7.9 Hz,1H), 7.78 (t, J = 7.7 Hz, 1H), 7.72 (dd, J = 8.5, 1.3azabicyclo[2.2.1]heptan- Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 4.51 (t, J =7.0 Hz, 2H), 4.28- 2-yl)-3-(6-methyl-2- 4.37 (m, 2H), 4.20 (t, J = 4.9Hz, 1H), 2.62 (s, 3H), 2.23-2.31 (m, pyridinyl)-1-propyl-1H- 1H),1.90-2.00 (m, 3H), 1.80-1.89 (m, 1H), 1.68-1.76 (m, 2H),indazole-6-carboxamide 1.60 (dd, J = 12.8, 4.6 Hz, 1H), 0.90 (t, J = 7.4Hz, 3H) 1-75 6-chloro-N-((1R,2R,4S)- 491.0 1H NMR (DMSO-d6) δ: 8.86 (d,J = 6.1 Hz, 1H), 8.65-8.75 (m, 7-cyano-7- 1H), 8.54-8.60 (m, 1H),8.00-8.09 (m, 2H), 7.65-7.75 (m, 1H), azabicyclo[2.2.1]heptan- 6.93-7.03(m, 1H), 5.20 (q, J = 9.0 Hz, 2H), 4.25-4.37 (m, 2H), 2-yl)-1-(6-(2,2,2-4.17 (t, J = 4.9 Hz, 1H), 2.20-2.31 (m, 1H), 2.04 (td, J = 8.6, 4.5trifluoroethoxy)-2- Hz, 1H), 1.79-1.89 (m, 1H), 1.68-1.78 (m, 1H),1.56-1.65 (m, pyridinyl)-1H-indazole- 1H), 1.40 (dd, J = 12.7, 4.3 Hz,1H) 5-carboxamide 1-76 6-chloro-N-((1R,2R,4S)- 443.8 1H NMR (DMSO-d6) δ:9.55 (s, 1H), 9.22 (s, 1H), 8.92 (br d, 7-cyano-7- J = 5.9 Hz, 1H),8.63-8.69 (m, 3H), 8.52 (d, J = 9.0 Hz, 1H), 8.12azabicyclo[2.2.1]heptan- (s, 1H), 7.99 (d, J = 5.5 Hz, 1H), 4.28-4.36(m, 2H), 4.18 (t, J = 4.9 2-yl)-1-(1,7- Hz, 1H), 2.22-2.30 (m, 1H),2.02-2.10 (m, 1H), 1.80-1.88 (m, naphthyridin-2-yl)-1H- 1H), 1.71-1.80(m, 1H), 1.58-1.67 (m, 1H), 1.41 (dd, J = 12.7, 4.0indazole-5-carboxamide Hz, 1H) 1-77 6-chloro-N-((1R,2R,4S)- 432.0 1H NMR(DMSO-d6) δ: 9.13 (s, 1H), 8.87 (br d, J = 6.0 Hz, 1H), 7-cyano-7- 8.58(s, 1H), 8.04-8.08 (m, 2H), 7.98 (d, J = 8.6 Hz, 1H), 7.34 (d,azabicyclo[2.2.1]heptan- J = 7.8 Hz, 1H), 4.46 (s, 2H), 4.29 (br s, 2H),4.16 (t, J = 4.7 Hz, 2-yl)-1-(6- 1H), 2.25 (br d, J = 2.9 Hz, 1H),2.01-2.07 (m, 1H), 1.83 (br d, (cyanomethyl)-2- J = 4.0 Hz, 1H), 1.74(br s, 1H), 1.61 (br s, 1H), 1.38-1.42 (m, pyridinyl)-1H-indazole- 1H)5-carboxamide 1-78 6-chloro-N-((1R,2R,4S)- 1H NMR (DMSO-d6) δ: 9.31 (s,1H), 9.12 (dd, J = 4.3, 1.9 Hz, 7-cyano-7- 1H), 8.93 (br d, J = 5.8 Hz,1H), 8.68 (s, 1H), 8.69 (d, J = 7.7 Hz, azabicyclo[2.2.1]heptan- 1H),8.54 (dd, J = 8.1, 1.9 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.122-yl)-1-(1,8- (s, 1H), 7.67 (dd, J = 8.0, 4.3 Hz, 1H), 4.29-4.36 (m,2H), 4.18 (t, naphthyridin-2-yl)-1H- J = 4.8 Hz, 1H), 2.23-2.31 (m, 1H),2.03-2.10 (m, 1H), 1.80-1.88 indazole-5-carboxamide (m, 1H), 1.71-1.80(m, 1H), 1.59-1.66 (m, 1H), 1.42 (dd, J = 12.6, 4.2 Hz, 1H) 1-794-(3-chlorophenyl)-N- 359 1H NMR (600 MHz, DMSO-d6) d 9.07 (d, J = 6.60Hz, 1H), 8.56 ((1R,2R,4S)-7-cyano-7- (s, 1H), 8.18 (s, 1H), 8.05 (d, J =7.90 Hz, 1H), 7.52 (t, J = 8.03 Hz, azabicyclo[2.2.1]heptan- 1H), 7.47(d, J = 8.01 Hz, 1H), 4.29 (br d, J = 4.52 Hz, 2H), 4.192-yl)-1,3-thiazole-2- (s, 1H), 3.21-3.41 (m, 2H), 1.68-1.86 (m, 4H)carboxamide 1-80 N-((1R,2R,4S)-7-cyano- 330.8 1H NMR (DMSO-d6, 600 MHz)Shift 8.55 (br d, 1H, J = 6.0 Hz), 7- 8.2-8.3 (m, 2H), 7.75 (dd. 1H, J =2.9, 5.0 Hz), 7.71 (dd, 1H, azabicyclo[2.2.1]heptan- J = 1.3, 5.1 Hz),4.2-4.3 (m, 2H), 4.18 (t, 1H, J = 4.8 Hz), 2.2-2.22-yl)-2(3-thiophenyl)- (m, 1H), 1.7-1.9 (m, 3H), 1.7-1.7 (m, 2H)1,3-thiazole-4- carboxamide 1-81 1-(3-chlorophenyl)-N- 341.8 1H NMR(DMSO-d6, 600 MHz) δ 8.67 (d, 1H, J = 2.6 Hz), 8.59((1R,2R,4S)-7-cyano-7- (d, 1H, J = 6.1 Hz), 8.11 (t, 1H, J = 2.0 Hz),7.95 (ddd, 1H, J = 0.8, azabicyclo[2.2.1]heptan- 2.1, 8.3 Hz), 7.58 (t,1H, J = 8.1 Hz), 7.45 (d, 1H, J = 8.0 Hz), 6.93 2-yl)-1H-pyrazole-3- (d,1H, J = 2.6 Hz), 4.2-4.3 (m, 2H), 4.17 (t, 1H, J = 4.8 Hz), 2.2-carboxamide 2.2 (m, 1H), 1.8-1.9 (m, 1H), 1.7-1.8 (m, 4H) 1-821-(3-chlorophenyl)-N- 355.8 1H NMR (DMSO-d6, 600 MHz) δ 8.51 (d, 1H, J =6.2 Hz), 7.7- ((1R,2R,4S)-7-cyano-7- 7.8 (m, 1H), 7.5-7.6 (m, 3H), 6.68(d, 1H, J = 0.7 Hz), 4.2-4.3 (m, azabicyclo[2.2.1]heptan- 1H), 4.20 (t,1H, J = 4.6 Hz), 4.1-4.2 (m, 1H), 2.3-2.4 (m, 3H), 2-yl)-5-methyl-1H-2.1-2.2 (m, 1H), 1.7-1.9 (m, 3H), 1.6-1.7 (m, 2H) pyrazole-3-carboxamide1-83 N-((1R,2R,4S)-7-cyano- 338.8 1H NMR (DMSO-d6, 600 MHz) δ 8.69 (d,1H, J = 6.0 Hz), 8.36 7- (t, 1H, J = 1.5 Hz), 8.09 (td, 1H, J = 1.2, 8.0Hz), 8.02 (s, 1H), 7.80 azabicyclo[2.2.1]heptan- (td, 1H, J = 1.2, 7.9Hz), 7.54 (t, 1H, J = 7.7 Hz), 4.2-4.3 (m, 2H), 2-yl)-3-(2-methyl-1,3-4.17 (t, 1H, J = 4.9 Hz), 2.74 (s, 3H), 2.2-2.3 (m, 1H), 1.8-1.9 (m,thiazol-4-yl)benzamide 2H), 1.6-1.7 (m, 2H), 1.58 (dd, 1H, J = 4.7, 12.8Hz) 1-84 7-bromo-N-((1R,2R,4S)- 386.8 1H NMR (DMSO-d6, 600 MHz) δ 11.14(br s, 1H), 8.90 (br d, 7-cyano-7- 1H, J = 5.4 Hz), 8.31 (d, 1H, J = 2.1Hz), 7.95 (dd, 1H, J = 2.1, 8.4 azabicyclo[2.2.1]heptan- Hz), 7.78 (d,1H, J = 8.5 Hz), 7.29 (s, 1H), 4.15-4.29 (m, 3H),2-yl)-1-oxo-1,2-dihydro- 2.16-2.28 (m, 1H), 1.79-1.96 (m, 2H), 1.64-1.75(m, 2H), 1.48- 3- 1.54 (m, 1H) isoquinolinecarboxamide 1-85N-((1R,2R,4S)-7-cyano- 311 1H NMR (600 MHz, DMSO-d6) Shift 8.28 (br d, J= 5.60 Hz, 7- 1H), 7.15 (t, J = 7.58 Hz, 2H), 6.59 (t, J = 7.24 Hz, 1H),6.53 (dd, azabicyclo[2.2.1]heptan- J = 2.65, 8.25 Hz, 2H), 4.08-4.14 (m,3H), 3.44 (td, J = 8.62, 16.85 2-yl)-1-phenyl-3- Hz, 1H), 3.30-3.37 (m,1H), 3.21-3.28 (m, 2H), 3.10 (quin, pyrrolidinecarboxamide J = 7.75 Hz,1H), 2.05-2.21 (m, 3H), 1.78-1.87 (m, 2H), 1.57-1.70 (m, 2H), 1.23-1.30(m, 1H) 1-86 N-((1R,2R,4S)-7-cyano- 325 1H NMR (600 MHz, DMSO-d6) Shift8.22 (br d, J = 6.38 Hz, 7- 1H), 7.15 (t, J = 7.57 Hz, 2H), 6.51-6.59(m, 3H), 4.04-4.20 (m, azabicyclo[2.2.1]heptan- 4H), 3.32-3.38 (m, 1H),3.09-3.16 (m, 1H), 3.03 (td, J = 7.16, 2-yl)-2-methyl-1-phenyl- 12.30Hz, 1H), 2.31-2.41 (m, 1H), 2.14-2.25 (m, 1H), 1.95-2.06 3- (m, 1H),1.79-1.93 (m, 2H), 1.55-1.74 (m, 2H), 1.26 (ddd, pyrrolidinecarboxamideJ = 4.52, 7.63, 12.46 Hz, 1H) 0.91 (dd, J = 3.11, 6.23 Hz, 3H) 1-87(3S)-N-((1R,2R,4S)-7- 354 1H NMR (600 MHz, DMSO-d6) Shift 8.32 (br t, J= 4.98 Hz, cyano-7- 1H), 7.55 (d, J = 14.32 Hz, 1H), 7.42 (d, J = 8.56Hz, 1H), 6.75 (dt, azabicyclo[2.2.1]heptan- J = 4.13, 8.91 Hz, 1H),4.05-4.14 (m, 3H), 3.61-3.70 (m, 1H), 2-yl)-1-(4-cyano-2- 3.46-3.59 (m,3H), 3.07 (dquin, J = 2.26, 7.53 Hz, 1H), 2.12-2.21 fluorophenyl)-3- (m,2H), 1.99-2.08 (m, 1H), 1.78-1.86 (m, 2H), 1.56-1.69 (m,pyrrolidinecarboxamide 2H), 1.22-1.30 (m, 1H) 1-88 1-(3-chlorophenyl)-N-345.0 1H NMR (500 MHz, CHLOROFORM-d) Shift 7.11-7.18 (m,((1R,2R,4S)-7-cyano-7- 1H), 6.70 (d, J = 7.79 Hz, 1H), 6.56 (d, J = 1.95Hz, 1H), 6.46 (dd, azabicyclo[2.2.1]heptan- J = 2.14, 8.24 Hz, 1H), 5.87(br s, 1H), 4.30-4.37 (m, 2H), 4.06 (t, 2-yl)-3- J = 5.00 Hz, 1H),3.45-3.53 (m, 3H), 3.29-3.45 (m, 1H), 2.99-3.07 pyrrolidinecarboxamide(m, 1H), 2.42-2.50 (m, 1H), 2.23-2.34 (m, 2H), 2.01-2.10 (m, 1H), 1.91(br t, J = 12.72 Hz, 1H), 1.71-1.85 (m, 1H), 1.56 (tdd, J = 4.18, 8.50,12.59 Hz, 1H), 1.03 (dd, J = 4.02, 12.85 Hz, 1H) 1-89N-((1R,2R,4S)-7-cyano- 307.8 1H NMR (600 MHz, DMSO-d6) Shift 8.49 (br d,J = 5.45 Hz, 7 1H), 7.90 (br d, J = 7.63 Hz, 2H), 7.49 (br t, J = 7.71Hz, 2H), azabicyclo[2.2.1]heptan- 7.37-7.42 (m, 1H), 7.25 (d, J = 3.43Hz, 1H), 7.11 (d, J = 3.43 Hz, 2-yl)-5-phenyl-2- 1H), 4.23-4.30 (m, 2H),4.18 (t, J = 4.75 Hz, 1H), 2.15-2.31 (m, furancarboxamide 1H), 1.79-1.92(m, 2H), 1.65-1.75 (m, 2H), 1.59 (br dd, J = 4.36, 12.77 Hz, 1H) 1-90N-(1R,2R,4S)-7-cyano- 350 1H NMR (600 MHz, DMSO-d6) Shift 8.48 (br d, J= 4.98 Hz, 7 1H), 7.67-7.75 (m, 2H), 7.41 (t, J = 7.63 Hz, 1H),7.23-7.30 (m, azabicyclo[2.2.1]heptan- 2H), 7.11 (d, J = 3.43 Hz, 1H),4.22-4.30 (m, 2H), 4.18 (br t, 2-yl)-5-(3-(2- J = 4.67 Hz, 1H), 2.96(td, J = 6.75, 13.74 Hz, 1H), 2.23 (br s, 1H), propanyl)phenyl)-2-1.78-1.93 (m, 2H), 1.66-1.75 (m, 2H), 1.58 (br dd, J = 3.89, 12.61furancarboxamide Hz, 1H), 1.26 (d, J = 6.85 Hz, 7H) 1-91N-(1R,2R,4S)-7-cyano- 375.8 1H NMR (600 MHz, DMSO-d6) Shift 8.58 (br d,J = 4.67 Hz, 7- 1H), 8.18-8.22 (m, 2H), 7.74 (d, J = 4.67 Hz, 2H), 7.35(d, J = 3.43 azabicyclo[2.2.1]heptan- Hz, 1H), 7.29 (d, J = 3.58 Hz,1H), 4.27 (br s, 2H), 4.19 (t, J = 4.67 2-yl)-5-(3- Hz, 1H), 2.25 (br s,1H), 1.82-1.91 (m, 2H), 1.68-1.73 (m, 2H), (trifluoromethyl)phenyl)-1.58 (br dd, J = 4.05, 12.77 Hz, 1H) 2-furancarboxamide 1-921-(3-chlorophenyl)-N- 358.8 1H NMR (600 MHz, DMSO-d6) Shift 8.12-8.20(m, 1H), 7.16- ((1R,2R,4S)-7-cyano-7- 7.23 (m, 1H), 6.92-6.95 (m, 1H),6.87-6.91 (m, 1H), 6.72-6.77 azabicyclo[2.2.1]heptan- (m, 1H), 4.02-4.16(m, 3H), 3.60-3.79 (m, 2H), 2.77-2.85 (m, 2-yl)-3- 1H), 2.66-2.75 (m,1H), 2.12-2.22 (m, 1H), 1.77-1.92 (m, 3H), piperidinecarboxamide1.46-1.75 (m, 5H), 1.21-1.29 (m, 2H) 1-93 N-((1R,2R,4S)-7-cyano- 394.81H NMR (600 MHz, DMSO-d6) Shift 8.67 (d, J = 4.83 Hz, 1H), 7 8.14 (d, J= 6.15 Hz, 1H), 6.99 (d, J = 4.83 Hz, 1H), 4.64 (br d,azabicyclo[2.2.1]heptan- J = 12.22 Hz, 2H), 4.03-4.14 (m, 3H), 2.99 (brt, J = 12.69 Hz, 2H), 2-yl)-1-(4- 2.45-2.48 (m, 1H), 2.12-2.18 (m, 1H),1.74-1.85 (m, 4H), 1.55- (trifluoromethyl)-2- 1.66 (m, 2H), 1.45-1.54(m, 2H), 1.25 (dd, J = 4.48, 12.65 Hz, pyrimidinyl)-4- 1H)piperidinecarboxamide 1-94 1-(3-bromophenyl)-N- 391 1H NMR (400 MHz,METHANOL-d4) Shift 7.03-7.09 (m, 1H), ((1R,2R,4S)-7-cyano-7- 6.67-6.77(m, 2H), 6.49-6.56 (m, 1H), 4.21-4.29 (m, 2H), 4.07-azabicyclo[2.2.1]heptan- 4.14 (m, 1H), 3.46-3.54 (m, 1H), 3.36-3.44 (m,2H), 3.29-3.35 2-yl)-3- (m, 3H), 3.12-3.22 (m, 1H), 2.15-2.40 (m, 2H),1.89-1.99 (m, pyrrolidinecarboxamide 2H), 1.80-1.88 (m, 1H), 1.64-1.73(m, 1H), 1.27-1.35 (m, 2H) 1-95 1-(3-chloro-4- 413 1H NMR (400 MHz,METHANOL-d4) Shift 7.49 (d, J = 8.81 Hz, (trifluoromethyl)phenyl)- 1H),6.68 (s, 1H), 6.55 (br d, J = 8.81 Hz, 1H), 4.21-4.29 (m, 2H),N-((1R,2R,4S)-7-cyano- 4.11 (t, J = 4.87 Hz, 1H), 3.35-3.61 (m, 4H),3.21 (t, J = 7.57 Hz, 7- 1H), 2.19-2.39 (m, 3H), 1.78-2.03 (m, 3H),1.65-1.78 (m, 1H), azabicyclo[2.2.1]heptan- 1.31 (dd, J = 4.25, 12.65Hz, 1H) 2-yl)-3- pyrrolidinecarboxamide 1-96 6-chloro-N-((1R,2R,4S)- 3321H NMR (600 MHz, DMSO-d6) Shift 8.42 (br t, J = 5.80 Hz, 7-cyano-7- 1H),7.16-7.24 (m, 1H), 7.10 (dd, J = 2.41, 8.72 Hz, 1H), 6.79azabicyclo[2.2.1]heptan- (dd, J = 3.19, 8.72 Hz, 1H), 4.30-4.37 (m, 1H),4.06-4.15 (m, 3H), 2-yl)-3,4-dihydro-2H- 3.87-3.98 (m, 1H), 2.79-2.98(m, 3H), 2.14-2.22 (m, 1H), 1.77- chromene-3- 1.88 (m, 2H), 1.55-1.69(m, 2H), 1.25 (dd, J = 4.40, 12.73 Hz, carboxamide 1H) 1-972-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.85 (d, J =5.7 Hz, 1 H), 7-cyano-7- (ESI): 8.15 (d, J = 1.6 Hz, 1 H), 8.07 (dd, J =8.0, 1.6 Hz, 1 H), 7.72- azabicyclo[2.2.1]heptan- 393.3 7.87 (m, 2 H),7.55 (d, J = 8.0 Hz, 1H), 7.33 (dd, J = 7.3, 1.3 Hz, 12-yl)-4-(6-cyclopropyl- (M + H)⁺. H), 4.28 (t, J = 3.8 Hz, 2 H), 4.16(t, J = 4.9 Hz, 1 H), 2.13-2.26 2-pyridinyl)benzamide (m, 2 H), 2.02(ddd, J = 12.8, 9.1, 3.8 Hz, 1 H), 1.67-1.78 (m, 2 H), 1.55-1.67 (m, 1H), 1.39 (dd, J = 12.8, 3.9 Hz, 1 H), 0.96- 1.06 (m, 4 H). 2-21-(3-chlorophenyl)-N- 359.2 1H NMR (600 MHz, DMSO-d6) Shift 8.13 (br d,J = 6.15 Hz, ((1R,2R,4S)-7-cyano-7- 1H), 7.13-7.24 (m, 1H), 6.93 (s,1H), 6.89 (d, J = 8.62 Hz, 1H), azabicyclo[2.2.1]heptan- 6.75 (dd, J =1.21, 7.82 Hz, 1H), 4.03-4.14 (m, 3H), 3.71-3.79 (m, 2-yl)-4- 2H),2.68-2.75 (m, 2H), 2.29-2.37 (m, 1H), 2.11-2.20 (m, 1H),piperidinecarboxamide 1.69-1.84 (m, 4H), 1.55-1.68 (m, 4H), 1.25 (dd, J= 4.59, 12.69 Hz, 1H) 2-3 N-((1R,2R,4S)-7-cyano- 393 1H NMR (600 MHz,DMSO-d6) Shift 8.13 (d, J = 6.23 Hz, 1H), 7- 6.93 (d, J = 1.56 Hz, 2H),6.81 (s, 1H), 4.08-4.12 (m, 2H), 4.06 azabicyclo[2.2.1]heptan- (br dd, J= 4.75, 11.05 Hz, 1H), 3.81 (br, J = 12.85 Hz, 2H), 2.77 2-yl)-1-(3,5-(br t, J = 12.53 Hz, 2H), 2.33-2.39 (m, 1H), 2.10-2.20 (m, 1H),dichlorophenyl)-4- 1.75-1.82 (m, 3H), 1.72 (br d, J = 14.71 Hz, 2H),1.55-1.63 (m, piperidinecarboxamide 3H), 1.25 (dd, J = 4.52, 12.69 Hz,1H) 2-4 (3S)-N-((1R,2R,4S)-7- 326 1H NMR (600 MHz, DMSO-d6) Shift 8.27(br s, 1H), 7.87-7.95 cyano-7- (m, 1H), 6.36-6.41 (m, 1H), 6.23-6.28 (m,1H), 4.06-4.15 (m, azabicyclo[2.2.1]heptan- 4H), 3.58-3.64 (m, 1H),3.46-3.52 (m, 1H), 3.39-3.44 (m, 1H), 2-yl)-1-(4-methyl-2- 3.02-3.10 (m,1H), 2.13-2.18 (m, 2H), 2.02-2.12 (m, 1H), 1.78- pyridinyl)-3- 1.88 (m,2H), 1.57-4.69 (m, 2H), 1.25-1.28 (m, 1H) pyrrolidinecarboxamide 2-5(3S)-N-((1R,2R,4S)-7- 337 1H NMR (600 MHz, DMSO-d6) Shift 8.34 (d, J =6.05 Hz, 1H), cyano-7- 8.16-8.22 (m, 2H), 7.32 (dd, J = 1.83, 2.75 Hz,1H), 4.07-4.18 (m, azabicyclo[2.2.1]heptan- 3H), 3.51 (dd, J = 8.16,9.63 Hz, 1H), 3.39-3.44 (m, 2H), 3.13 2-yl)-1-(5-cyano-3- (quin, J =7.57 Hz, 1H), 2.13-2.27 (m, 2H), 2.00-2.13 (m, 1H), pyridinyl)-3-1.76-1.88 (m, 2H), 1.55-1.72 (m, 2H), 1.22-1.31 (m, 1H)pyrrolidinecarboxamide 2-6 (3S)-N-((1R,2R,4S)-7- 342 1H NMR (600 MHz,DMSO-d6) Shift 8.31 (s, 1H), 7.70-7.78 cyano-7- (m, 2H), 6.20 (dd, J =2.11, 5.96 Hz, 1H), 5.70-5.76 (m, 1H), azabicyclo[2.2.1]heptan-4.05-4.17 (m, 3H), 3.76 (s, 3H), 3.41-3.48 (m, 1H), 3.21-3.382-yl)-1-(2-methoxy-4- (m, 3H), 3.06-3.13 (m, 1H), 2.12-2.23 (m, 2H),2.01-2.10 (m, pyridinyl)-3- 1H), 1.79-1.89 (m, 2H), 1.54-1.70 (m, 2H),1.21-1.30 (m, 1H) pyrrolidinecarboxamide 2-7 (3S)-N-((1R,2R,4S)-7- 3261H NMR (600 MHz, DMSO-d6) Shift 8.27 (d, J = 6.05 Hz, 1H), cyano-7- 7.35(dd, J = 7.24, 8.34 Hz, 1H), 6.39-6.42 (m, 1H), 6.20-6.23 (m,azabicyclo[2.2.1]heptan- 1H), 4.07-4.15 (m, 3H), 3.59-3.63 (m, 1H),3.46-3.51 (m, 1H), 2-yl)-1-(6-methyl-2- 3.38-3.42 (m, 1H), 3.32-3.36 (m,1H), 3.02-3.10 (m, 1H), 2.27- pyridinyl)-3- 2.29 (m, 3H), 2.13-2.20 (m,2H), 2.02-2.09 (m, 1H), 1.78-1.87 pyrrolidinecarboxamide (m, 2H),1.56-1.70 (m, 2H), 1.25-1.29 (m, 1H) 2-8 (3S)-N-((1R,2R,4S)-7- 327 1HNMR (600 MHz, DMSO-d6) Shift 8.31 (br d, J = 6.05 Hz, cyano-7- 1H), 7.74(s, 1H), 7.66 (s, 1H), 4.07-4.14 (m, 3H), 3.65 (dd,azabicyclo[2.2.1]heptan- J = 7.98, 10.36 Hz, 1H), 3.54 (ddd, J = 4.68,7.98, 10.09 Hz, 1H), 2-yl)-1-(6-methyl-2- 3.36-3.49 (m, 2H), 3.09 (quin,J = 7.52 Hz, 1H), 2.28 (s, 3H), pyrazinyl)-3- 2.15-2.27 (m, 2H), 2.08(br s, 1H), 1.78-1.91 (m, 2H), 1.56-1.70 pyrrolidinecarboxamide (m, 2H),1.21-1.33 (m, 1H) 2-9 N-((1R,2R,4S)-7-cyano- 393.2 1H NMR (600 MHz,DMSO-d6) Shift 7.91 (br t, J = 5.61 Hz, 7- 1H), 6.66 (d, J = 1.40 Hz,1H), 6.46 (dd, J = 1.75, 4.01 Hz, 2H), azabicyclo[2.2.1]heptan-4.02-4.16 (m, 3H), 3.62-3.69 (m, 1H), 3.08-3.13 (m, 1H), 2.34-2-yl)-1-(3,5- 2.40 (m, 1H), 2.06-2.17 (m, 1H), 1.87-1.94 (m, 1H),1.68-1.82 dichlorophenyl)-3- (m, 2H), 1.54-1.66 (m, 2H), 1.41-1.47 (m,1H), 1.24-1.34 (m, methyl-3- 4H) pyrrolidinecarboxamide 2-10N-((1R,2R,4S)-7-cyano- 397 1H NMR (600 MHz, DMSO-d6) Shift 8.77 (br s,1H), 6.74 (s, 7- 1H), 6.56-6.62 (m, 2H), 4.11-418 (m, 3H), 3.56-3.81 (m,3H), azabicyclo[2.2.1]heptan- 3.40-3.45 (m, 1H), 2.31-2.38 (m, 1H),2.07-2.19 (m, 1H), 1.57- 2-yl)-1-(3,5- 1.88 (m, 4H) dichlorophenyl)-3-fluoro-3- pyrrolidinecarboxamide 2-11 N-((1R,2R,4S)-7-cyano- 391 1H NMR(500 MHz, CHLOROFORM-d) Shift 8.04 (s, 1H), 7- 6.78 (t, J = 1.75 Hz,1H), 6.67 (d, J = 1.82 Hz, 2H), 4.31-4.40 (m, azabicyclo[2.2.1]heptan-2H), 4.06-4.11 (m, 1H), 3.80-3.91 (m, 1H), 3.31-3.50 (m, 2H),2-yl)-2-(3,5- 3.02-3.10 (m, 1H), 2.43-2.54 (m, 1H), 2.02-2.14 (m, 1H),1.78- dichlorophenyl)-2- 1.97 (m, 3H), 1.56-1.65 (m, 1H), 1.04-1.13 (m,1H), 0.76-0.95 azabicyclo[3.1.0]hexane- (m, 2H) 4-carboxamide 2-122-(3-chlorophenyl)-N- 341.4 1H NMR (600 MHz, DMSO-d6) Shift 8.71-8.83(m, 1H), 8.12 ((1R,2R,4S)-7-cyano-7- (t, J = 1.83 Hz, 1H), 8.06-8.09 (m,1H), 7.97 (s, 1H), 7.62-7.70 azabicyclo[2.2.1]heptan- (m, 2H), 4.25-4.31(m, 2H), 4.20 (s, 1H), 2.22-2.30 (m, 1H), 2-yl)-1,3-oxazole-5- 1.81-1.93(m, 2H), 1.66-1.74 (m, 2H), 1.54-1.59 (m, 1H) carboxamide 2-13(3S)-N-((1R,2R,4S)-7- 350 1H NMR (600 MHz, DMSO-d6) Shift 8.66-8.69 (m,1H), 8.03- cyano-7- 8.06 (m, 1H), 7.85-7.88 (m, 1H), 7.75-7.79 (m, 1H),7.44-7.49 azabicyclo[2.2.1]heptan- (m, 1H), 4.04-4.34 (m, 3H), 2.15-2.27(m, 1H), 1.77-1.91 (m, 2-yl)-1-(3- 2H), 1.64-1.72 (m, 2H), 1.53-1.59 (m,1H), 1.23-1.30 (m, 1H) (cyanomethyl)phenyl)-3- pyrrolidinecarboxamide2-14 (3S)-1-(3-chloro-5- 375 1H NMR (600 MHz, DMSO-d6) Shift 8.30 (br d,J = 6.18 Hz, methoxyphenyl)-N- 1H), 6.23-6.26 (m, 1H), 6.15 (s, 1H),5.99 (d, J = 1.91 Hz, 1H), ((1R,2R,4S)-7-cyano-7- 4.06-4.18 (m, 3H),3.73 (s, 3H), 3.34-3.50 (m, 2H), 3.21-3.27 azabicyclo[2.2.1]heptan- (m,2H), 3.18 (br d, J = 4.63 Hz, 1H), 3.06-3.1.2 (m, 1H), 2.39 (br 2-yl)-3-s, 1H), 2.18 (br t, J = 11.94 Hz, 2H), 1.97-2.12 (m, 1H), 1.76-1.87pyrrolidinecarboxamide (m, 1H), 1.55-1.70 (m, 1H), 1.22-1.32 (m, 1H)2-15 N-((1R,2R,4S)-7-cyano- 379 1H NMR (600 MHz, DMSO-d6) Shift 6.72(td, J = 1.68, 6.68 Hz, 7- 1H), 6.45 (s, 1H), 6.42 (s, 1H), 4.06-4.15(m, 3H), 4.01 (br dd, azabicyclo[2.2.1]heptan- J = 4.87, 10.70 Hz, 1H),3.39-3.55 (m, 1H), 3.23-3.30 (m, 1H), 2-yl)-1-(3,5- 2.11-2.27 (m, 2H),1.75-2.08 (m, 4H), 1.58-1.71 (m, 2H), 1.46- dichlorophenyl)-L- 1.57 (m,1H), 1.28-1.36 (m, 1H) prolinamide 2-16 3′-chloro-N- 352 1H NMR (600MHz, DMSO-d6) Shift 8.67 (br d, J = 5.99 Hz, ((1R,2R,4S)-7-cyano-7- 1H),8.11 (s, 1H), 7.89 (s, 1H), 7.87 (s, 1H), 7.80 (t, J = 1.71 Hz,azabicyclo[2.2.1]heptan- 1H), 7.70 (d, J = 8.33 Hz, 1H), 7.59 (t, J =7.93 Hz, 1H), 7.54 (t, 2-yl)[biphenyl]-3- J = 8.04 Hz, 1H), 7.47-7.50(m, 1H), 4.26-4.34 (m, 2H), 4.18 (t, carboxamide J = 4.90 Hz, 1H),2.21-2.26 (m, 1H), 1.86-1.92 (m, 1H), 1.79-1.86 (m, 1H), 1.66-1.72 (m,2H), 1.57 (dd, J = 4.71, 12.73 Hz, 1H) 2-17 N-((1R,2R,4S)-9-cyano- 4011H NMR (600 MHz, DMSO-d6) Shift 9.10 (br d, J = 5.99 Hz, 7- 1H), 8.68 (s1H), 7.78 (s, 1H), 7.68 (d, J = 8.63 Hz, 1H), 7.60azabicyclo[2.2.1]heptan- (dd, J = 2.63, 8.63 Hz, 1H), 7.55 (s, 1H), 4.34(br s, 1H), 4.24 (t, 2-yl)-4-(2,5- J = 4.68 Hz, 1H), 4.17 (t, J = 4.63Hz, 1H), 2.18 (s, 3H), 1.75-1.89 dichlorophenyl)-5- (m, 4H), 1.68 (br d,J = 9.99 Hz, 1H) methyl-2- pyridinecarboxamide 2-184-(3-chlorophenyl)-N- 367 1H NMR (600 MHz, DMSO-d6) Shift 9.07 (br d, J= 6.36 Hz, ((1R,2R,4S)-7-cyano-7- 1H), 8.63 (s, 1H), 7.83 (s, 1H),7.53-7.60 (m, 3H) 7.42-7.47 (m, azabicyclo[2.2.1]heptan- 1H), 4.34 (brdd, J = 4.90, 11.17 Hz, 1H), 4.24 (t, J = 4.63 Hz, 1H),2-yl)-5-methyl-2- 4.17 (t, J = 4.68 Hz, 1H), 2.34 (s, 3H), 2.16-2.24 (m,1H), 1.75- pyridinecarboxamide 1.88 (m, 4H), 1.68 (br d, J = 9.26 Hz,1H) 2-19 N-((1R,2R,4S)-7-cyano- 391 1H NMR (600 MHz, DMSO-d6) Shift 8.10(d, J = 6.08 Hz, 1H), 7- 7.53 (dd, J = 7.45, 8.45 Hz, 1H), 6.78 (d, J =7.74 Hz, 1H), 6.74 (d, azabicyclo[2.2.1]heptan- J = 8.70 Hz, 1H), 4.26(br d, J = 10.54 Hz, 2H), 4.02-4.15 (m, 3H), 2-yl)-1-(6-(1- 2.81 (br t,J = 12.72 Hz, 2H), 2.38-2.45 (m, 1H), 2.11-2.18 (m, cyanocyclopropyl)-2-1H), 1.76-1.84 (m, 2H), 1.45-1.73 (m, 6H), 1.26 (dd, J = 4.54,pyridinyl)-4- 12.62 Hz, 1H) piperidinecarboxamide 2-20N-((1R,2R,4S)-7-cyano- m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 9.12 (dd, J =2.4, 0.9 Hz, 7- (ESI): 1 H), 8.81 (d, J = 6.0 Hz, 1H), 8.31 (dd, J =8.3, 2.3 Hz, 1 H), 8.17 azabicyclo[2.2.1]heptan- 384.1(M + (dd, J = 8.4,0.9 Hz, 1 H), 8.08-8.13 (m, 2 H), 7.57 (d, J = 7.8 Hz, 2-yl)-6-(3-(1-H)+. 1H), 7.44-7.47 (m, 1 H), 4.34 (m, 1 H), 4.28 (m, 1 H), 4.20cyanocyclopropyl)phenyl)- (m, 1 H), 2.25 (m, 1 H), 1.91-1.96 (m, 1 H),1.79-1.85 (m, 3 1)-3-pyridinecarboxamide H), 1.71 (m, 2 H), 1.60-1.64(m, 2 H), 1.54 (d, J = 4.7 Hz, 1 H). 2-21 3-chloro-N-((1R,2R,4S)- m/z ¹HNMR(400 MHz, DMSO-d₆): δ ppm 8.85 (d, J = 5.7 Hz, 1H), 7-cyano-7- (ESI):7.89 (d, J = 1.8 Hz, 1H), 7.75 (dd, J = 8.0, 1.8 Hz, 1 H), 7.52 (d,azabicyclo[2.2.1]heptan- 410.1(M + J = 8.0 Hz, 1 H), 7.35 (ddd, J =10.0, 2.4, 1.5 Hz, 1 H), 7.32 (t, 2-yl)-3′-cyclopropyl-5′- H)+. J = 1.6Hz, 1 H), 6.93-6.99 (m, 1 H), 4.23-4.32 (m, 2 H), 4.16fluoro[biphenyl]-4- (t, J = 4.9 Hz, 1 H), 2.03 (m, 2 H), 1.67-1.87 (m, 2H), 1.54- carboxamide 1.65 (m, 1 H), 1.39 (dd, J = 12.8, 4.0 Hz, 1 H),1.24 (m, 1 H), 0.97-1.06 (m, 2 H), 0.79-0.87 (m, 2 H). 2-22N-((1R,2R,4S)-7-cyano- m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 9.34 (dd, J =2.2, 0.9 Hz, 7- (ESI): 1H), 9.14 (d, J = 6.7 Hz, 1 H), 8.63 (dd, J =8.2, 2.2 Hz, 1H), 8.13 azabicyclo[2.2.1]heptan- 385.2(M + (dd, J = 8.2,0.8 Hz, 1H). 8.09 (dd, J = 7.9, 1.0 Hz, 1 H), 8.03 (d, 2-yl)-6-(1- H)+.J = 7.8 Hz, 1 H), 7.61 (dd, J = 7.6, 0.9 Hz, 1 H), 4.35 (dt, J = 10.2,cyanocyclopropyl)[2,3′- 5.0 Hz, 1 H), 4.26 (t, J = 4.6 Hz, 1 H), 4.18(t, J = 4.4 Hz, 1 H), bipyridine]-6′- 2.20 (td, J = 11.5, 4.9 Hz, 1 H),1.75-1.91 (m, 8 H), 1.64-1.72 carboxamide (m, 1 H) 2-232-chloro-N-((1R,2R,4S- m/z ¹H NMR (400 MHz, DMSO-d₆): δ ppm 8.85 (d, J =5.8 Hz, 1 H), 7-cyano-7- (ESI): 8.13 (d, J = 1.7 Hz, 1 H), 8.06 (dd, J =8.0, 1.7 Hz, 1 H), 7.87- azabicyclo[2.2.1]heptan- 417.1(M + 7.95 (m,2H), 7.81 (dd, J = 6.3, 2.4 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 12-yl)-4-(6-(1- H)+ H), 4.28 (m, 2 H), 4.16 (t, J = 4.9 Hz, 1 H), 2.23(m, 1H), 1.92- ethynylcyclopropyl)-2- 2.09 (m, 1 H), 1.72-1.88 (m, 2 H),1.50-1.74 (m, 4 H), 1.46 pyridinyl)benzamide (m, 2 H), 1.38 (dd, J =12.8, 4.0 Hz, 1H) 2-24-1 2-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400 MHz,DMSO-d₆): δ ppm 8.85 (d, J = 5.8 Hz, 1 H), 7-cyano-7- (ESI): 7.88 (dd, J= 10.3, 1.8 Hz, 2 H) 7.76 (dd, J = 8.0, 1.8 Hz, 1 H),azabicyclo[2.2.1]heptan- 431.1(M + 7.69 (dd, J = 7.9, 1.8 Hz, 1H). 7.54(d, J = 8.0 Hz, 1H), 7.44 (d, 2-yl)-4-((3R)-3-cyano-3- H)+. J = 7.9 Hz,1 H), 4.28 (m, 2 H), 4.17 (t, J = 4.8 Hz, 1 H), 3.04 (t,methyl-2,3-dihydro-1H- J = 7.1 Hz, 2 H), 2.58-2.65 (m, 1 H), 2.22 (dt, J= 12.9), 7.5 Hz, 2 inden-5-yl)benzamide H), 2.03 (td, J = 8.6, 4.5 Hz, 1H), 1.82 (dt, J = 9.7, 5.2 Hz, 1 H), 1.72 (m, 4 H), 1.57-1.66 (m, 1 H),1.40 (dd, J = 12.8, 3.9 Hz, 1 H) 2-24-2 2-chloro-N-((1R,2R,4S)- m/z ¹HNMR(400 MHz, DMSO-d₆): δ ppm 8.85 (d, J = 5.8 Hz, 1 H), 7-cyano-7-(ESI): 7.88 (dd, J = 10.7, 1.8 Hz, 2 H), 7.76 (dd, J = 8.0, 1.8 Hz, 1H), azabicyclo[2.2.1]heptan- 431.2(M + 7.69 (dd, J = 7.9, 1.8 Hz, 1 H),7.54 (d, J = 8.0 Hz, 1 H), 7.44 (d, 2-yl)-4-((3S)-3-cyano-3- H)+. J =7.9 Hz, 1 H), 4.28 (m, 2H) 4.17 (t, J = 4.9 Hz, 1 H), 3.04 (t,methyl-2,3-dihydro-1H- J = 7.1 Hz, 2 H), 2.62 (dt, J = 13.5, 6.8 Hz, 1H), 2.22 (dt, J = 13.0, inden-5-yl)benzamide 7.5 Hz, 2 H), 2.03 (td, J =8.6, 4.4 Hz, 1 H), 1.82 (dt, J = 8.3, 4.4 Hz, 1 H), 1.72 (m, 4 H), 1.61(td, J = 9.1, 8.7, 4.6 Hz, 1 H), 1.40 dd, J = 12.8, 4.0 Hz, 1 H) 2-262-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.86 (d, J =5.8 Hz, 1 H), 7-cyano-7- (ESI): 8.22 (d, J = 1.6 Hz, 1 H), 8.14 (dd, J =8.0, 1.7 Hz, 1 H), 7.82- azabicyclo[2.2.1]heptan- 409.3 7.92 (m, 2 H),7.58 (d, J = 8.0 Hz, 1 H), 7.48 (dd, J = 7.0, 1.6 Hz, 12-yl)-4-(6-(2-methyl-2- (M + H)+. H), 4.29 (m, 2 H), 4.17 (t, J = 4.9Hz, 1 H), 2.46 (m, 1 H), 2.24 propanyl)-2- (m, 1 H), 1.97-2.08 (m, 1 H),1.75-1.85 (m, 1 H), 1.55- 1.66 pyridiny)benzamide (m, 1 H), 1.31-1.46(m, 1 H), 1.39 (s, 9 H). 2-27-2 (1S,6R,7R)-N- m/z ¹H NMR(400 MHz,DMSO-d₆): δ ppm 8.31 (d, J = 6.6 Hz, 1 H), ((1R,2R,4S)-7-cyano-7- (ESI):6.77 (m, 3 H), 4.08 (m, 3 H), 3.64 (m, 1 H), 3.49 (dd, J = 13.2, 3.3azabicyclo[2.2.1]heptan- 405.1 Hz, 1 H), 3.23 (m, 1 H), 3.03 (m, 1 H),2.10-2.20 (m, 1 H), 2-yl)-3-(3,5- (M + H)+. 2.04 (m, 1 H), 1.83 (m, 3H), 1.66 (m, 1 H), 1.55 (m, 4 H), 1.17 dichlorophenyl)-3- (dd, J = 12.7,4.6 Hz, 1 H). azabicyclo[4.1.0]heptane- 7-carboxamide 2-27-1(1R,6S,7R)-N- m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.31 (d, J = 6.6 Hz, 1H), ((1R,2R,4S)-7-cyano-7- (ESI): 6.77 (m, 3 H), 4.08 (m, 3 H), 3.64 (m,1 H), 3.49 (dd, J = 13.2, 3.3 azabicyclo[2.2.1]heptan- 405.1 Hz, 1 H),3.23 (m, 1 H), 3.03 (m, 1 H), 2.10-2.20 (m, 1 H), 2-yl)-3-(3,5- (M +H)+. 2.04 (m, 1 H), 1.83 (m, 3 H), 1.66 (m, 1 H), 1.55 (m, 4 H), 1.17dichlorophenyl)-3- (dd, J = 12.7, 4.6 Hz, 1 H).azabicyclo[4.1.0]heptane- 7-carboxamide 2-29 N-((1R,2R,4S)-7-cyano- m/z¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.31 (d, J = 6.6 Hz, 1 H), 7- (ESI):6.79 (t, J = 1.6 Hz, 2 H), 6.75 (dt, J = 3.3, 1.7 Hz, 1 H), 4.04-4.14azabicyclo[2.2.1]heptan- 405.1 (m, 3 H), 3.60-3.66 (m, 1 H), 3.49 (dd, J= 13.1, 3.7 Hz, 1 H), 2-yl)-3-(3,5- (M + H)+. 3.21 (m, 1 H), 2.99-3.08(m, 1 H), 2.15 (m, 1 H), 2.06 (m, 1 dichlorophenyl)-3- H), 1.83 (m, 3H), 1.51-1.62 (m, 5 H), 1.12-1.24 (m, 1 H). azabicyclo[4.1.0]heptane-7-carboxamide 2-30 N-((1R,2R,4S)-7-cyano- m/z, ¹H NMR(400 MHz, DMS0-d₆):δ ppm 8.18 (d, J = 5.9 Hz, 1 H), 7- (ESI): 7.36 (ddd, J = 8.5, 7.3, 4.4Hz, 1 H), 6.37-6.65 (m, 2 H), 3.61- azabicyclo[2.2.1]heptan- 366.3 4.71(m, 5 H), 2.63-2.88 (m, 2 H), 2.25-2.41 (m, 1 H), 2.06-2-yl)-1-(6-cyclopropyl- (M + H)+. 2.21 (m, 1 H), 1.70-1.96 (m, 4 H),1.62 (m, 4 H), 1.29-1.45 2-pyridinyl)-3- (m, 1 H), 1.25 (m, 1 H),0.68-0.95 (m, 4 H). piperidinecarboxamide 2-31-2 (1S,5S)-N-((1R,2R,4S)-m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 7.74 (d, J = 5.7 Hz, 1 H),7-cyano-7- (ESI): 6.75 (t, J = 1.8 Hz, 1 H), 6.56 (d, J = 1.8 Hz, 2 H),4.13 (m, 3 H), azabicyclo[2.2.1]heptan- 393.0 3.65 (d, J = 9.7 Hz, 1H),3.50-3.58 (m, 2 H), 3.26-3.32 (m, 1 2-yl)-3-(3,5- (M + 2H)+. H), 2.14(m, 2 H), 1.74-1.87 (m, 2 H), 1.65 (m, 2 H), 1.34- dichlorophenyl)-3-1.50 (m, 2 H), 0.80 (t, J = 4.7 Hz, 1 H), azabicyclo[3.1.0]hexane-1-carboxamide 2-31-2 (1R,5R)-N-((1R,2S,4S)- m/z ¹H NMR(400 MHz,DMSO-d₆): δ ppm 7.74 (d, J = 5.7 Hz, 1 H), 7-cyano-7- (ESI): 6.75 (t, J= 1.8 Hz, 1H), 6.56 (d, J = 1.8 Hz, 2 H), 4.13 (m, 3 H),azabicyclo[2.2.1]heptan- 393.0 3.65 (d, J = 9.7 Hz, 1 H), 3.50-3.58 (m,2 H), 3.26-3.32 (m, 1 2-yl)-3-(3,5- (M + 2H)+. H), 2.14 (m, 2 H),1.74-1.87 (m, 2 H), 1.65 (m, 2 H), 1.34- dichlorophenyl)-3- 1.50 (m, 2H), 0.80 (t, J = 4.7 Hz, 1 H), azabicyclo[3.1.0]hexane- 1-carboxamide2-33 (1R,5S)-N-((1R,2R,4S)- m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 7.74(dd, J = 5.7, 2.6 Hz, 7-cyano-7- (ESI): 1 H), 6.75 (q, J = 1.7 Hz, 1 H),6.56 (d, J = 1.8 Hz, 2 H), 4.13 (m, 3 azabicyclo[2.2.1]heptan- 393.1 H),3.52-3.66 (m, 3 H), 2.14 (m, 2 H), 1.83 (m, 2 H), 1.60- 2-yl)-3-(3,5-(M + 2H)+. 1.72 (m, 2 H), 1.37-1.48 (m, 2 H), 0.79 (m, 1 H).dichlorophenyl)-3- azabicyclo[3.1.0]hexane- 1-carboxamide 2-34(3S)-N-((1R,2R,4S)-7- m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.17 (t, J =5.6 Hz, 1 H), cyano-7- (ESI): 7.53 (ddd, J = 8.5, 7.4, 5.2 Hz, 1 H),6.41-7.04 (m, 2 H), 3.77- azabicyclo[2.2.1]heptan- 391.3 4.79 (m, 5 H),2.75-3.03 (m, 2 H), 2.26-2.38 (m, 1 H), 2.03- 2-yl)-1-(6-(1- (M + H)+.2.23 (m, 1 H), 1.72-1.95 (m, 3 H), 1.38-1.74 (m, 7 H), 1.05-cyanocyclopropyl)-2- 1.38 (m, 2 H). pyridinyl)-3- piperidinecarboxamide2-35 N-((1R,2R,4S)-7-cyano- m/z ¹H NMR (400 MHz, DMSO-d₆): δ ppm 8.46(d, J = 6.1 Hz, 1 H), 7- (ESI): 8.14 (dt, J = 8.2, 1.0 Hz, 1H), 7.80 (d,J = 8.6 Hz, 1H) 7.45 (ddd, azabicyclo[2.2.1]heptan- 350.3(M + J = 8.4,6.9, 1.2 Hz, 1 H), 7.27 (ddd, J = 7.9, 6.9, 0.9 Hz, 1 H), 5.242-yl)-1-cyclopentyl-1H- H)+. (m, 1 H), 4.33 (m, 2 H), 4.19 (d, J = 4.6Hz, 1 H), 2.07-2.27 (m, indazole-3-carboxamide 5 H), 1.86-1.96 (m, 3 H),1.68-1.82 (m, 6 H). 2-36 N-((1R,2R,4S)-7-cyano- m/z ¹H NMR(400 MHz,DMSO-d₆): δ ppm 7.35 (dd, J = 8.5, 7.2 Hz, 7- (ESI): 1 H), 6.53 (dd, J =9.2, 7.8 Hz, 2 H), 4.25 (d, J = 13.1 Hz, 2 H), azabicyclo[2.2.1]heptan-366.1 3.96-4.12 (m, 3 H), 2.65-2.77 (m, 2 H), 2.30-2.46 (m, 2 H),2-yl)-1-(6-cyclopropyl- (M + H)+. 2.14 (t, J = 11.5 Hz, 1H) 1.89 (m, 1H)1.73-1.82 (m, 2 H), 2-pyrdinyl)-4- 1.55-1.70 (m, 3 H), 1.48 (m, 2 H),1.25 (m, 1 H), 1.03 (dd, piperidinecarboxamide J = 18.1, 6.7 Hz, 1 H),0.71-0.94 (m, 4 H). 2-37 N-((1R,2R,4S)-7-cyano- m/z ¹H NMR(400 MHz,DMSO-d₆): δ ppm 9.55 (s, 1 H), 9.05 (d, 7- (ESI): J = 6.4 Hz, 1 H), 8.09(d, J = 1.8 Hz, 2 H), 7.77 (t, J = 1.8 Hz, 1 H),azabicyclo[2.2.1]heptan- 377.1(M + 4.28-4.38 (m, 1 H), 4.25 (m, 1 H),4.17 (t, J = 4.4 Hz, 1 H), 2.19 2-yl)-1-(3,5- H)+ (td, J = 12.2, 11.8,4.5 Hz, 1 H), 1.66-1.90 (m, 5 H). dichlorophenyl)-1H- 1,2,4-triazole-3-carboxamide 2-38 2-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400 MHz, DMSO-d₆): δppm 8.92 (d, J = 5.7 Hz, 1 H), 7-cyano-7- (ESI): 8.75 (dd, J = 13.8, 2.4Hz, 2 H), 7.69 (d, J = 1.5 Hz, 1 H), 7.51- azabicyclo[2.2.1]heptan-421.1(M + 7.61 (m, 2 H), 4.29 (m, 2 H), 4.17 (t, J = 4.9 Hz, 1 H), 2.24(m, 1 2-yl)-4-(6-(2-cyano-2- H)+ H), 2.03 (m, 1 H), 1.82 (m, 2 H), 1.74(m, 1 H), 1.67 (m, 6 H), propanyl)-2- 1.55-1.64 (m, 1 H).pyrazinyl)benzamide 2-39-1 2-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400 MHz,DMSO-d₆): δ ppm 8.55 (d, J = 5.6 Hz, 1 H), 7-cyano-7- (ESI): 7.30 (d, J= 8.6 Hz, 1 H), 7.04 (d, J = 2.5 Hz, 1 H), 6.97 (dd, J = 8.6,azabicyclo[2.2.1]heptan- 384.3 2.5 Hz, 1 H), 4.23 (dp, J = 7.2, 4.0 Hz,2 H), 4.14 (t, J = 4.9 Hz, 1 2-yl)-4-(3S)-3-cyano-1- (M + H)⁺. H), 3.53(d, J = 5.2 Hz, 2 H), 3.21-3.32 (m, 2 H), 3.07 (dq,piperidinyl)benzamide J = 7.4, 4.8 Hz, 1 H), 2.13-2.25 (m, 1 H),1.75-2.01 (m, 4 H), 1.53-1.75 (m, 4 H), 1.40 (dd, J = 12.8, 4.0 Hz, 1H). 2-39-2 2-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm8.55 (d, J = 5.6 Hz, 1 H), 7-cyano-7- (ESI): 7.30 (d, J = 8.6 Hz, 1 H),7.04 (d, J = 2.5 Hz, 1 H), 6.97 (dd, J = 8.6, azabicyclo[2.2.1]heptan-384.3 2.5 Hz, 1 H), 4.23 (dp, J = 7.2, 4.0 Hz, 2 H), 4.14 (t, J = 4.9Hz, 1 2-yl)-4-((3R)-3-cyano-1- (M + H)⁺. H), 3.53 (d, J = 5.2 Hz, 2 H),3.21-3.32 (m, 2 H), 3.07 (dq, piperidinyl)benzamide J = 7.4, 4.8 Hz, 1H), 2.13-2.25 (m, 1 H), 1.75-2.01 (m, 4 H), 1.53-1.75 (m, 4 H), 1.40(dd, J = 12.8, 4.0 Hz, 1 H). 2-41 2-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400MHz, DMSO-d₆): δ ppm 8.54 (d, J = 5.6 Hz, 1 H), 7-cyano-7- (ESI): 7.30(d, J = 8.7 Hz, 1 H), 7.04 (d, J = 2.5 Hz, 1 H), 6.97 (dd, J = 8.7,azabicyclo[2.2.1]heptan- 384.3 2.5 Hz, 1 H), 4.22 (dd, J = 5.5, 3.1 Hz,2 H), 4.14 (t, J = 4.9 Hz, 1 2-yl)-4-((3S)-3-cyano-1- (M + H)⁺. H), 3.53(d, J = 5.2 Hz, 2 H), 3.28 (dt, J = 11.1, 3.8 Hz, 2 H), 3.07piperidinyl)benzamide (dq, J = 10.0, 4.8 Hz, 1 H), 2.17 (d, J = 13.0 Hz,1 H), 1.75-1.99 (m, 4 H), 1.69 (q, J = 3.9 Hz, 2 H), 1.61 (ddt, J =11.0, 8.8, 4.1 Hz, 2 H), 1.39 (dd, J = 12.8, 4.0 Hz, 1 H), 2-422-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.86 (br s,1H), 7.83 (dd, 7-cyano-7- (ESI): J = 16.7, 1.8 Hz, 2 H), 7.73 (dd, J =8.0, 1.8 Hz, 1 H), 7.66 (dd, azabicyclo[2.2.1]heptan- 431.2(M + J = 7.9,1.8 Hz, 1 H), 7.52 (d, J = 8.0 Hz, 1 H), 7.44 (d, J = 7.9 Hz, 12-yl)-4-((3R)-3-cyano-3- H)⁺, H), 4.26 (q, J = 3.3, 2.1 Hz, 2 H), 4.15(t, J = 4.9 Hz, 1 H), 3.03 (t, methyl-2,3-dihydro-1H- J = 7.1 Hz, 2 H),2.61 (t, J = 6.6 Hz, 1 H), 2.18-2.27 (m, 2 H), inden-5-yl)benzamide 2.00(td, J = 8.6, 4.5 Hz, 1 H), 1.78-1.86 (m, 1 H), 1.69 (s, 4 H), 1.57-1.64(m, 1 H), 1.38 (dd, J = 12.8, 4.0 Hz, 1 H). 2-43-12-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.43 (d, J =5.6 Hz, 1 H), 7-cyano-7- (ESI): 7.28 (d, J = 8.6 Hz, 1 H), 6.55-6.65 (m,2 H), 4.22 (s, 2 H), 4.13 azabicyclo[2.2.1]heptan- 410.1 (t, J = 4.9 Hz,1 H), 4.00-4.13 (m, 1 H) 3.50 (dd, J = 10.6, 5.2 2-yl)-4-((1S,2S,5R)-2-(M + H)⁺. Hz, 1H) 3.21 (d, J = 10.5 Hz, 1 H), 3.13 (dd, J = 12.5, 5.0Hz, 1 cyano-6- H), 2.78 (s, 1 H), 2.53-2.58 (m, 1H), 2.43-2.48 (m, 1 H),azobicyclo[3.2.1]octan- 2.18 (s, 1 H), 1.93 (dt, J = 18.5, 12.8 Hz, 2H), 1.57-1.82 (m, 2 6-yl)benzamide H), 1.36-1.52 (m, 2 H), 1.39 (s, 2H),1.15-1.26 (m, 1 H). 2-44 N-((1R,2R,4S)-7-cyano- m/z ¹H NMR(400 MHz,DMSO-d₆): δ ppm 8.72 (d, J = 2.7 Hz, 1 H), 7- (ESI): 8.61 (d, J = 6.1Hz, 1 H), 8.49 (t, J = 2.0 Hz, 1 H), 8.34 (dd, J = 7.8,azabicyclo[2.2.1]heptan- 333.3 2.4 Hz, 1 H), 7.87 (d, J = 7. 7 Hz, 1 H),7.78 (t, J = 8.0 Hz, 1 H), 2-yl)-1-(3-cyanophenyl)- (M + H)+ 6.97 (d,2.6 Hz, 1 H), 4.28 (dt, J = 14.5, 4.7 Hz, 2 H) 4.18 (t, 1H-pyrazole-3- J= 4.7 Hz, 1 H), 2.20 (d, J = 12.6 Hz, 1 H), 1.64-1.90 (m, 5 H)carboxamide 2-45 2-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400 MHz, DMSO-d₆): δppm 8.88 (d, J = 5.8 Hz, 1 H), 7-cyano-7- (ESI): 8.27 (d, J = 1.7 Hz, 1H), 8.19 (dd, J = 8.0, 1.7 Hz, 1 H), 8.10 (dd, azabicyclo[2.2.1]heptan-431.1 J = 7.9, 1.0 Hz, 1 H), 8.04 (t, J = 7.8 Hz, 1 H), 7.58-7.68 (m, 22-yl)-4-(6-(1- (M + H)⁺ H), 4.28 (m, 2 H), 4.17 (t, J = 4.9 Hz, 1 H),2.72-2.92 (m, 3 H), cyanocyclobutyl)-2- 2.20-2.36 (m, 1 H), 2.12-2.22(m, 1 H), 1.97-2.10 (m, 2 H), pyridinyl)benzamide 1.77-1.90 (m, 3 H),1.53-1.68 (m, 1 H), 1.39 (dd, J = 12.7, 3.9 Hz, 1 H) 2-46-2(2S)-N-((1R,2R,4S)-7- m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 7.83 (d, J =5.9 Hz, 1 H), cyano-7- (ESI): 7.49 (d, J = 2.0 Hz, 1 H), 7.41 (d, J =2.0 Hz, 2 H), 4.10 (t, J = 4.9 azabicyclo[2.2.1]heptan- 379.1 Hz, 1 H),4.05-3.95 (m, 2 H), 3.54-3.71 (m, 3 H), 3.27 (m, 1 2-yl)-1-(3,5- (M +H)⁺. H), 2.98 (m, 1 H), 2.14-2.26 (m, 1 H), 2.08 (m, 2 H), 1.65-dichlorobenzyl)-2- 1.80 (m, 1 H), 1.39-1.60 (m, 3 H), 1.34 (dd, J =12.8, 4.1 Hz, 1 H) azetidinecarboxamide 2-46-3 (2R)-N-((1R,2R,4S)-7- m/z¹H NMR(400 MHz, DMSO-d₆): δ ppm 7.87 (d, J = 6.3 Hz, 1 H), cyano-7-(ESI): 7.48 (d, J = 2.0 Hz, 1 H), 7.40 (d, J = 2.0 Hz, 2 H), 4.10 (t, J= 5.0 azabicyclo[2.2.1]heptan- 379.1 Hz, 1 H), 4.03 (d, J = 4.4 Hz, 1H),3.88 (m, 1 H), 3.49-3.74 (m, 2-yl)-1-(3,5- (M + H)⁺. 3 H), 3.34 (m, 1H),3.00 (m, 1 H), 2.12-2.24 (m, 1 H), 1.93- dichlorobenzyl)-2- 2.15 (m, 2H), 1.75 (m, 1 H), 1.59 (m, 3 H), 1.28 (dd, J = 12.7, 4.8azetidinecarboxamide Hz, 1 H) 2-48-1 2-chloro-N-((1R,2R,4S)- m/z ¹HNMR(400 MHz, DMSO-d₆): δ ppm 8.43 (d, J = 5.5 Hz, 1 H), 7-cyano-7-(ESI): 7.30 (d, J = 8.4 Hz, 1 H), 6.37-6.69 (m, 2 H), 4.22 (t, J = 3.4Hz, azabicyclo[2.2.1]heptan- 384.2 2H), 4.14 (t, J = 5.0 Hz, 1 H),3.41-3.54 (m, 1 H), 3.39 (td, 2-yl)-4-(3S)-3- (M + H)+. J = 5.9, 3.0 Hz,1 H), 3.25-3.31 (m, 1 H), 3.02 (dd, J = 9.9, 6.9 (cyanomethyl)-1- Hz, 1H) 2.59-2.81 (m, 3 H), 2.19 (dtd, J = 11.8, 7.1, 4.5 Hz, 2pyrrolidinyl)benzamide H), 1.96 (ddd, J = 11.9, 8.6, 3.9 Hz, 1H),1.70-1.86 (m, 2 H), 1.50-1.67 (m, 2 H), 1.42 (dd, J = 12.8, 4.0 Hz, 1H). 2-48-2 2-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm8.43 (d, J = 5.5 Hz, 1 H), 7-cyano-7- (ESI): 7.30 (d, J = 8.4 Hz, 1 H),6.37-6.69 (m, 2 H), 4.22 (t, J = 3.4 Hz, azabicyclo[2.2.1]heptan- 384.22 H), 4.14 (t, J = 5.0 Hz, 1 H), 3.41-3.54 (m, 1 H), 3.39 (td,2-yl)-4-((3R)-3- (M + H)⁺. J = 5.9, 3.0 Hz, 1 H), 3.25-3.31 (m, 1 H),3.02 (dd, J = 9.9, 6.9 (cyanomethyl)-1- Hz, 1 H), 2.59-2.81 (m, 3 H),2.19 (dtd, J = 11.8, 7.1, 4.5 Hz, 2 pyrrolidinyl)benzamide H), 1.96(ddd, J = 11.9, 8.6, 3.9 Hz, 1 H), 1.70-1.86 (m, 2 H), 1.50-1.67 (m, 2H), 1.42 (dd, J = 12.8, 4.0 Hz, 1 H). 2-50 N-((1R,2R,4S)-7-cyano- m/z ¹HNMR(400 MHz, DMSO-d₆): δ ppm 8.92 (d, J = 6.3 Hz, 1 H), 7- (ESI): 8.41(dd, J = 2.1, 1.5 Hz, 1 H), 8.24-8.33 (m, 2 H), 7.98 (ddt,azabicyclo[2.2.1]heptan- 383.2 J = 7.8, 4.3, 1.1 Hz, 2 H), 7.86 (t, J =8.0 Hz, 1 H), 7.61 (ddd, 2-yl)-1(3-cyanophenyl)- (M + H)⁺. J = 8.5, 6.9,1.2 Hz, 1 H), 7.44 (ddd, J = 7.9, 6.9, 0.8 Hz, 1 H), 4.40 1H-indazole-3-(dt, J = 10.0, 4.8 Hz, 1 H), 4.33 (t, J = 4.6 Hz, 1 H), 4.19 (t, J = 4.7carboxamide Hz, 1 H), 2.23 (td, J = 11.4, 3.7 Hz, 1 H), 1.94 (ddd, J =12.3, 8.4, 4.5 Hz, 1 H), 1.65-1.85 (m, 4 H). 2-51 (3R)-N-((1R,2R,4S)-7-m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.08 (dd, J = 6.3, 2.6 Hz, cyano-7-(ESI): 1 H), 7.49 (td, J = 2.0, 0.8 Hz, 1 H), 7.36 (d, J = 1.9 Hz, 2 H),4.04- azabicyclo[2.2.1]heptan- 393.1 4.11 (m, 3 H), 3.58 (d, J = 4.9 Hz,2 H), 2.88 (p, J = 7.4 Hz, 1 H), 2-yl)-1-(3,5- (M + H)⁺ 2.76 (td, J =8.5, 6.6 Hz, 1 H), 2.63 (td, J = 9.4, 7.9, 3.8 Hz, 1 H),dichlorobenzyl)-3- 2.31-2.46 (m, 2 H), 2.06-2.24 (m, 1 H), 1.84-2.04 (m,2 H), pyrrolidinecarboxamide 1.72-1.87 (m, 2H), 1.51-1.69 (m, 2 H), 1.21(dt, J = 12.6, 4.5 Hz, 1 H) 2-52 (3S)-N-((1R,2R,4S)-7- m/z ¹H NMR(400MHz, DMSO-d₆): δ ppm 8.33 (t, J = 5.2 Hz, 1H), cyano-7- (ESI): 7.49 (dd,J = 8.4, 7.3 Hz, 1 H), 6.75 (d, J = 7.2 Hz, 1 H), 6.35 (dd,azabicyclo[2.2.1]heptan- 377.4 J = 8.2, 1.9 Hz, 1 H), 4.07-4.16 (m, 3H), 3.53-3.63 (m, 1 H), 2-yl)-1-(6-(1- (M + H)⁺. 3.38-343 (m, 1 H), 3.28(s, 1H), 3.06 (p, J = 7.7 Hz, 1 H), 2.14-2.22 cyanocyclopropyl)-2- (m, 2H), 2.04 (td, J = 9.4, 8.7, 4.2 Hz, 2 H), 1.82 (d, J = 7.3 pyridinyl)-3-Hz, 2 H), 1.55-1.80 (m, 6 H), 1.20-1.30 (m, 1 H). pyrrolidinecarboxamide2-43-2 2-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.43(d, J = 5.6 Hz, 1 H), 7-cyano-7- (ESI): 7.28 (d, J = 8.6 Hz, 1 H),6.55-6.65 (m, 2 H), 4.22 (s, 2 H), 4.13 azabicyclo[2.2.1]heptan- 410.1(t, J = 4.9 Hz, 1 H), 4.00-4.13 (m, 1 H), 3.50 (dd, J = 10.6, 5.22-yl)-4-((2R)-2-cyano-6- (M + H)⁺ Hz, 1 H), 3.21 (d, J = 10.5 Hz, 1 H),3.13 (dd, J = 12.5, 5.0 Hz, 1 azabicyclo[3.2.1]octan- H), 2.78 (s, 1H),2.53-2.58 (m, 1H), 2.43-2.48 (m, 1 H), 6-yl)benzamide 2.18 (s, 1 H),1.93 (dt, J = 18.5, 12.8 Hz, 2 H), 1.57-1.82 (m, 2 H), 1.36-1.52 (m, 2H), 1.39 (s, 2 H), 1.15-1.26 (m, 1 H). 2-54 2-chloro-N-((1R,2R,4S)- m/z¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.68 (d, J = 5.6 Hz, 1 H), 7-cyano-7-(ESI): 7.41 (d, J = 8.5 Hz, 1 H), 7.13 (d, J = 2.5 Hz, 1 H), 7.01 (dd, J= 8.6, azabicyclo[2.2.1]heptan- 371.1 2.5 Hz, 1 H), 4.19-4.29 (m, 2 H),4.15 (t, J = 4.9 Hz, 1 H), 4.12 2-yl)-4-((1- (M + H)⁺ (s, 2H), 2.20 (s,1 H), 1.98 (ddd, J = 12.7, 9.1, 4.0 Hz, 1 H), 1.78cyanocyclopropyl)meth- (m, 2 H), 1.60 (ddd, J = 12.3, 9.1, 3.8 Hz, 1 H),1.32-1.43 (m, 3 oxy)benzamide H), 1.10-1.26 (m, 2 H) 2-55N-((1R,2R,4S)-7-cyano- m/z ¹H NMR(400 MHz, Chloroform-d): δ ppm7.73-7.83 (m, 2 H), 7- (ESI): 7.69 (dd, J = 7.8, 0.9 Hz, 1 H), 7.57-7.65(m, 2 H), 7.55 (d, azabicyclo[2.2.1]heptan- 424.3 J = 8.0 Hz, 1 H), 6.14(d, J = 5.7 Hz, 1 H), 4.59 (dt, J = 10.9, 4.9 Hz, 2-yl)-4-(6-(1- (M +H)⁺. 1 H), 4.53 (t, J = 14.3 Hz, 1 H), 4.13 (t, J = 4.9 Hz, 1 H),2.53-2.65 cyanocyclopropyl)-2- (m, 1 H), 2.24-2.35 (m, 1 H), 2.05-2.15(m, 1 H)1.82-2.07 pyridinyl)-2- (m, 4 H), 1.75-1.82 (m, 2 H), 1.07-1.16(m, 3 H), 0.86 (ddt, cyclopropylbenzamide J = 7.7, 4.6. 2.6 Hz, 3 H)2-56 2-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400 MHz, DMSO-d6), δ ppm 8.77(d, J = 5.7 Hz, 1H), 7-cyano-7- (ESI): 7.33 (dd, J = 8.3, 7.6 Hz, 1 H),7.07 (dd, J = 8.4, 1.4 Hz, 1 H), 7.01 azabicyclo[2.2.1]heptan- 371.0(dd, J = 7.6, 1.4 Hz, 1 H), 5.03-5.15 (m, 1H) 4.24 (s, 2 H), 4.142yl)-3-((cis-3- (M + H)+. (t, J = 4.9 Hz, 1 H), 3.42-3.53 (m, 1 H), 2.86(dddd, J = 11.4, 7.1, cyanocyclobutyl)oxy)benzamide 4.7, 2.6 Hz, 2 H),2.56 (t, J = 1.9 Hz, 2 H), 2.20 (s, 1 H), 1.98 (ddd, J = 12.6, 9.0, 3.8Hz, 1 H), 1.78 (s, 2 H), 1.57 (ddd, J = 11.2, 9.1, 3.7 Hz, 1H),1.31-1.42 (m, 1 H). 2-57 2-chloro-N-((1S,2R,4R)- m/z ¹H NMR(400 MHz,DMSO-d₆): δ ppm 8.43 (d, J = 5.6 Hz, 1 H), 7-cyano-7- (ESI): 7.30 (d, J= 8.5 Hz, 1 H), 6.12-6.69 (m, 2 H), 4.22 (h, J = 5.4, 4.6azabicyclo[2.2.1]heptan- 384.2 Hz, 2 H), 4.14 (t, J = 4.9 Hz, 1 H), 3.48(dd, J = 9.9, 7.2 Hz, 1 H), 2-yl)-4-((3R)-3- (M + H)⁺. 3.23-3.41 (m, 4H), 3.02 (dd, J = 9.9, 6.8 Hz, 1 H), 2.63-2.77 (cyanomethyl)-1- (m, 2H),2.10-2.25 (m, 1 H), 1.96 (ddd, J = 11.9, 8.5, 3.8 Hz, 2pyrrolidinyl)benzamide H), 1.68-1.87 (m, 2 H), 1.55-1.71 (m, 1 H), 1.42(dd, J = 12.7, 4.1 Hz, 1 H). 2-58 2-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400MHz, DMSO-d₆): δ ppm 8.66 (d, J = 5.7 Hz, 1 H), 7-cyano-7- (ESI): 7.38(d, J = 8.5 Hz, 1 H), 7.02 (d, J = 2.4 Hz, 1 H), 6.91 (dd, J = 8.5,azabicyclo[2.2.1]heptan- 371.0 2.4 Hz, 1H), 5.02-5.14 (m, 1 H),4.19-4.28 (m, J = 4.1 Hz, 2 2-yl)-4-((cis-3- (M + H)⁺. 1H), 4.14 (t, J =4.9 Hz, 1 H), 3.36-3.52 (m, 1 H), 2.83 (dddd,cyanocyclobutyl)oxy)benzamide J = 11.6, 7.1, 4.8, 2.5 Hz, 2 H),2.42-2.51 (m, 2 H) 2.20 (s, 1 1H), 1.97 (ddd, J = 12.7, 9.0, 3.9 Hz,1H), 1.67-1.83 (m, 2 H), 1.59 (ddd, J = 12.3, 9.2, 3.8 Hz, 1 H), 1.37(dd, J = 12.8, 4.0 Hz, 1 H). 2-59 2-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400MHz, DMSO-d₆): δ ppm 8.88 (d, J = 5.8 Hz, 1 H), 7-cyano-7- (ESI): 8.27(d, J = 1.7 Hz, 1 H), 8.16 (td, J = 8.2, 1.3 Hz, 2 H), 8.08 (t,azabicyclo[2.2.1]heptan- 468.1 J = 7.8 Hz, 1 H), 7.73 (dd, J = 7.6, 0.9Hz, 1 H), 7.62 (d, J = 8.0 Hz, 2-yl)-4-(6-(1-cyano-3,3- (M + H)⁺. 1 H),4.28 (t, J = 4.3 Hz, 2 H), 4.17 (t, J = 4.9 Hz, 1 H), 3.55-3.65difluorocyclobutyl)-3- (m, 4 H), 2.24 (s, 1 H), 2.00-2.06 (m, 1 H), 1.82(d, J = 11.8 Hz, pyridinyl)benzamide 1H), 1.74 (d, J = 13.0 Hz, 1 H),1.61 (td, J = 9.4, 4.9 Hz, 1 H), 1.39 (dd, J = 12.8, 4.0 Hz, 1 H) 2-602-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.87 (d, J =5.9 Hz, 1 H), 7-cyano-7- (ESI): 7.44-7.54 (m, 4 H), 7.34-7.39 (m, 3 H),4.27 (q, J = 5.4, 4.2 azabicyclo[2.2.1]heptan- 417.1 Hz, 2 H), 4.16 (t,J = 4.9 Hz, 1 H), 2.21 (d, J = 11.7 Hz, 1 H), 2.01 2-yl)-3′-(1- (M +H)⁺. (ddd, J = 12.8, 9.1, 3.9 Hz, 1 H), 1.81 (td, J = 4.8, 3.1 Hz, 3 H),cyanocyclopropyl)[bi- 1.73 (dd, J = 14.8, 3.7 Hz, 1 H), 1.55-1.61 (m, 3H), 1.37 (dd, phenyl]-3-carboxamide J = 12.7, 4.0 Hz, 1 H) 2-61-22-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.52 (d, J =5.6 Hz, 1 H), 7-cyano-7- (ESI): 7.30 (d, J = 8.6 Hz, 1 H), 6.97 (d, J =2.4 Hz, 1 H), 6.91 (dd, J = 8.7, azabicyclo[2.2.1]heptan- 398.2 2.5 Hz,1 H), 4.23 (tq, J = 7.7, 4.7, 4.1 Hz, 2 H), 4.14 (t, J = 4.92-yl)-4-((3S)-3- (M + H)⁺. Hz, 1 H), 3.65-3.84 (m, 2 H), 2.79 (td, J =12.7, 12.2, 3.0 Hz, 1 (cyanomethyl)-1- H), 2.63-2.70 (m, 1 H), 2.59 (dd,J = 20.4, 3.8 Hz, 2 H), 2.46 (t, piperidinyl)benzamide J = 1.8 Hz, 1 H),2.22 (m, 1 H), 1.97 (ddd, J = 12.4, 8.9, 3.9 Hz, 1 H), 1.82-1.93 (m, 1H), 1.65-1.82 (m, 2 H), 1.47-1.64 (m, 2 H), 1.36-1.47 (m, 1 H),1.20-1.35 (m, 1 H), 1.06-1.20 (m, 1 H). 2-61-1 2-chloro-N-((1R,2R,4S)-m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.52 (d, J = 5.6 Hz, 1 H),7-cyano-7- (ESI): 7.30 (d, J = 8.6 Hz, 1 H), 6.97 (d, J = 2.4 Hz, 1 H),6.91 (dd, J = 8.7, azabicyclo[2.2.1]heptan- 398.2 2.5 Hz, 1 H), 4.23(tq, J = 7.7, 4.7, 4.1 Hz, 2 H), 4.14 (t, J = 4.9 2-yl)-4-((3R)-3- (M +H)⁺. Hz, 1 H), 3.65-3.84 (m, 2 H), 2.79 (td, J = 12.7, 12.2, 3.0 Hz, 1(cyanomethyl)-1- H), 2.63-2.70 (m, 1 H), 2.59 (dd, J = 20.4, 3.8 Hz, 2H), 2.46 (t, piperidinyl)benzamide J = 1.8 Hz, 1 H), 2.22 (m, 1 H), 1.97(ddd, J = 12.4, 8.9, 3.9 Hz, 1 H), 1.82-1.93 (m, 1 H), 1.65-1.82 (m, 2H), 1.47-1.64 (m, 2 H), 1.36-1.47 (m, 1 H), 1.20-1.35 (m, 1 H),1.06-1.20 (m, 1 H). 2-63 3-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400 MHz,DMSO-d6): δ ppm 8.86 (d, J = 5.8 Hz, 1 H), 7-cyano-7- (ESI): 7.94 (d, J= 1.8 Hz, 1 H), 7.79 (dd, J = 7.9, 1.8 Hz, 1 H), 7.49-azabicyclo[2.2.1]heptan- 435.1 7.66 (m, 2 H), 7.47 (t, J = 1.6 Hz, 1 H),7.26 (dt, J = 9.8, 2.0 Hz, 1 2-yl)-3′-(1- (M + H)⁺. H), 4.28 (q, J =6.7, 4.5 Hz, 2 H), 4.16 (t, J = 4.9 Hz, 1 H), 2.24 (d,cyanocyclopropyl)-5′- J = 9.4 Hz, 1 H), 2.01 (ddd, J = 12.6, 9.0, 3.8Hz, 1 H), 1.77-1.90 fluoro[biphenyl]-4- (m, 3 H), 1.63-1.79 (m, 3 H),1.60 (ddd, J = 12.1, 9.3, 3.7 Hz, 1 carboxamide H), 1.39 (dd, J = 12.8,3.9 Hz, 1 H). 2-64 2-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400 MHz, DMSO-d₆):δ ppm 8.81 (d, J = 5.7 Hz, 1 H), 7-cyano-7- (ESI): 8.31 (s, 1 H), 7.92(d, J = 2.2 Hz, 1 H), 7.80 (dd, J = 8.5, 2.1 Hz, 1azabicyclo[2.2.1]heptan- 396.1 H), 7.53 (d, J = 8.5 Hz, 1 H), 4.27 (q, J= 5.9, 3.6 Hz, 2 H), 4.16 (t, 2-yl)-4-(4,5,6,7- (M + H)⁺. J = 4.9 Hz, 1H), 2.62-2.72 (m, 2 H), 2.57 (t, J = 6.1 Hz, 2 H),tetrahydro-1H-indazol-1- 2.22 (s, 1 H), 2.00 (ddd, J = 12.7, 9.0, 3.8Hz, 1 H), 1.79 (q, yl)benzamide J = 5.9, 4.9 Hz, 2 H), 1.72 (s, 4 H),1.55-1.66 (m, 1 H), 1.39 (dd, J = 12.8, 4.0 Hz, 1 H). 2-652-chloro-N-((1R,2R,4S)- m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.81 (d, J =5.6 Hz, 1 H), 7-cyano-7- (ESI): 8.23 (s, 1 H), 7.92 (d, J = 2.1 Hz, 1H), 7.80 (dd, J = 8.4, 2.2 Hz, 1 azabicyclo[2.2.1]heptan- 382.3 H), 7.53(d, J = 8.4 Hz, 1 H), 4.27 (q, J = 5.8, 3.5 Hz, 2 H), 4.16 (t,2-yl)-4-(5,6- (M + H)⁺. J = 4.9 Hz, 1 H), 2.68 (dt, J = 14.9, 7.1 Hz, 4H), 2.34-2.44 (m, dihydrocyclopenta[c]pyrazol- 2 H), 2.22 (s, 1 H), 2.00(ddd, J = 12.8, 9.1, 3.9 Hz, 1 H), 1.75 (s, 1(4H)-yl)benzamide 1 H),1.60 (ddd, J = 12.4, 9.0, 3.7 Hz, 1 H), 1.39 (dd, J = 12.8, 4.0 Hz, 1H), 1.15 (t, J = 7.2 Hz, 1 H) 2-66 2-chloro-N-((1R,2R,4S)- m/z ¹HNMR(400 MHz, DMSO-d₆): δ ppm 8.81 (d, J = 5.7 Hz, 1 H), 7-cyano-7-(ESI): 8.24 (s, 1 H), 7.92 (d J = 2.2 Hz, 1 H), 7.80 (dd, J = 8.4, 2.2Hz, 1 azabicyclo[2.2.1]heptan- 382.1 H), 7.47-7.61 (m, 1 H), 4.27 (q, J= 6.2, 3.5 Hz, 2 H), 4.16 (t, 2-yl)-4-(5,6- (M + H)+, J = 4.9 Hz, 1 H),2.89 (d, J = 15.6 Hz, 1 H), 2.67 (dt, J = 14.9, 7.2dihydrocyclopenta[c]pyrazol- Hz, 2 H), 2.38 (q, J = 7.3 Hz, 1 H),2.10-2.28 (m, 1 H), 2.00 2(4H)-yl)benzamide (ddd, J = 12.7, 9.0, 3.8 Hz,1 H), 1.65-1.82 (m, 2 H), 1.60 (ddd, J = 12.1, 9.1, 3.7 Hz, 1 H),1.25-1.44 (m, 2 H), 1.03 (s, 1 H). 2-67 2-chloro-N-((1R,2R,4S)- m/z ¹HNMR(400 MHz, DMSO-d₆): δ ppm 8.52 (d, J = 5.6 Hz, 1 H), 7-cyano-7-(ESI): 7.30 (d, J = 8.6 Hz, 1 H), 6.97 (d, J = 2.5 Hz, 1 H), 6.91 (dd, J= 8.7, azabicyclo[2.2.1]heptan- 398.2 2.5 Hz, 1 H), 4.23-4.14 (m, 3 H),3.64-3.84 (m, 2H), 2.78 2-yl)-4-(3S)-3- (M + H)⁺ (ddd, J = 12.7, 11.4,3.0 Hz, 1 H), 2.59-2.71 (m, 2 H) 2.53- (cyanomethyl)-1- 2.58 (m, 1 H),2.18 (dt, J = 11.3, 7.4 Hz, 1 H), 1.80-2.04 (m, 3 piperidinyl)benzamideH), 1.64-1.80 (m, 3 H), 1.46-1.63 (m, 2 H), 1.22-1.45 (m, 2 H). 5-16N-((1R,2R,4S)-7-cyano- m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.24 (t, J =5.3 Hz, 1 H), 7- (ESI): 6.54-6.87 (m, 3 H), 4.10 (dt, J = 19.7, 5.1 Hz,3 H), 3.61-3.84 azabicyclo[2.2.1]heptan- 407.2 (m, 2 H), 3.38-3.44 (m, 1H), 3.24 (dd, J = 14.2, 8.7 Hz, 1 H), 2-yl)-1-(3,5- (M + H)⁺ 2.71-2.81(m, 1 H), 2.18 (q, J = 13.1, 10.5 Hz, 1 H), 1.73-1.98 dichlorophenyl)-3-(m, 4 H), 1.45-1.72 (m, 4 H), 1.20-1.38 (m, 2 H) azepanecarboxamide 7-3(3S)-6-chloro-N- 397.0 1H NMR (DMSO-d₆) δ: 7.40 (s, 1H), 7.36 (d, J =8.6 Hz, 1H), ((1R,2R,4S)-7-cyano-7- 7.03 (dd, J = 8.6, 2.0 Hz, 1H),4.39-4.48 (m, 1H), 4.24-4.30 (m, azabicyclo[2.2.1]heptan- 1H), 4.18 (t,J = 4.8 Hz, 1H), 3.60 (s, 3H), 3.04 (br s, 4H), 2.73-2-yl)-N,9-dimethyl- 2.88 (m, 3H), 2.50-2.68 (m, 1H), 2.08 (br d, J =11.6 Hz, 2H), 2,3,4,9-tetrahydro-1H- 1.77-1.85 (m, 2H), 1.66-1.75 (m,4H) carbazole-3-carboxamide 7-4 N-((1R,2R,4S)-7-cyano- 431.0 1H NMR(DMSO-d6) δ: 8.50 (s, 1H), 8.40 (d, J = 11.0 Hz, 1H), 7- 8.01 (br d, J =6.5 Hz, 1H), 7.87 (t, J = 8.2 Hz, 1H), 7.76 (d, J = 8.2azabicyclo[2.2.1]heptan- Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 4.51 (br s,1H), 4.46 (br s, 1H), 2yl)-1-(6-cyclopropyl- 4.24 (br s, 1H), 2.92 (brs, 3H), 2.21-2.29 (m, 1H), 2.17-2.21 (m, 2-pyridinyl)-6-fluoro-N- 1H),1.71-1.93 (m, 5H), 1.07-1.19 (m, 4H) methyl-1H-indazole-5- carboxamide7-5 6-chloro-N-((1R,2R,4S)- 420.8 1H NMR (DMSO-d6) δ: 8.94 (s, 1H), 8.52(s, 1H), 7.97 (br s, 7-cyano-7- 1H), 7.92 (t, J = 7.9 Hz, 1H), 7.81 (d,J = 8.3 Hz, 1H), 7.24 (d, azabicyclo[2.2.1]heptan- J = 7.5 Hz, 1H), 4.56(br s, 1H), 4.50 (br s, 1H), 4.26 (br s, 1H), 2-yl)-N-methyl-1-(6- 2.82(s, 3H), 2.62 (s, 3H), 2.14-2.25 (m, 1H), 1.80-1.93 (m, 4H),methyl-2-pyridinyl)-1H- 1.74 (br d, J = 7.9 Hz, 1H)indazole-5-carboxamide 7-6 N-((1R,2R,4S)-7-cyano- 405.0 1H NMR (DMSO-d6)δ: 8.61 (d, J = 10.9 Hz, 1H), 8.51 (s, 1H), 7 8.01 (br d, J = 6.5 Hz,1H), 7.92 (t, J = 7.8 Hz, 1H), 7.82 (d, J = 8.2 azabicyclo[2.2.1]heptan-Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 4.51 (br s, 1H), 4.46 (br s, 1H),2-yl)-6-fluoro-N-methyl- 4.24 (br s, 1H), 2.91 (br s, 3H), 2.62 (s, 3H),2.52-2.56 (m, 1H), 1-(6-methyl-2- 2.08-2.26 (m, 1H), 1.79-1.92 (m, 3H),1.65-1.78 (m, 1H) pyridinyl)-1H-indazole- 5-carboxamide 7-7N-((1R,2R,4S)-7-cyano- 400.4 1H NMR (DMSO-d6) δ: 8.67 (d, J = 8.5 Hz,1H), 7.92 (d, J = 7.9 7- Hz, 1H), 7.81 (s, 1H), 7.78 (t, J = 7.7 Hz,1H), 7.30 (dd, J = 8.3, 1.2 azabicyclo[2.2.1]heptan- Hz, 1H), 7.24 (d, J= 7.7 Hz, 1H), 4.45 (br s, 1H), 4.29-4.39 (m, 2-yl)-N,1-dimethyl-3-(6-1H), 4.19-4.25 (m, 1H), 4.17 (s, 3H), 2.96 (s, 3H), 2.61 (s, 3H),methyl-2-pyridinyl)-1H- 2.19 (br s, 1H), 1.84-1.95 (m, 2H), 1.72-1.84(m, 3H) indazole-6-carboxamide 7-8 (3R)-1-(3-chlorophenyl)- 359.2 1H NMR(500 MHz, CHLOROFORM-d) Shift 7.14 (t, J = 8.11 N-((1R,2R,4S)-7-cyano-Hz, 1H), 6.68 (dd, J = 1.23, 7.85 Hz, 1H), 6.55 (t, J = 2.14 Hz, 1H), 7-6.45 (dd, J = 1.95, 8.30 Hz, 1H), 4.49-4.56 (m, 1H), 4.32-4.49 (m,azabicyclo[2.2.1]heptan- 1H), 4.13 (br s, 1H), 3.36-3.57 (m, 4H), 3.10(br s, 3H), 2.21- 2-yl)-N-methyl-3- 2.37 (m, 2H), 2.10 (br s, 1H), 1.94(br s, 1H), 1.69 (br dd, pyrrolidinecarboxamide J = 4.02, 13.10 Hz, 2H),1.55-1.63 (m, 3H) 7-9 (3S)-1-(3-chlorophenyl)- 359.2 1H NMR (500 MHz,CHLOROFORM-d) Shift 7.14 (t, J = 8.11 N-((1R,2R,4S)-7-cyano- Hz, 1H),6.68 (dd, J = 1.23, 7.85 Hz, 1H), 6.55 (t, J = 2.08 Hz, 1H), 7- 6.45(dd, J = 2.08, 8.30 Hz, 1H), 4.39-4.55 (m, 2H), 4.13 (br s,azabicyclo[2.2.1]heptan- 1H), 3.55-3.60 (m, 1H), 3.35-3.53 (m, 4H),3.03-3.17 (m, 3H), 2-yl)-N-methyl-3- 2.21-2.39 (m, 3H), 2.10 (br s, 1H),1.83-2.02 (m, 1H), 1.54-1.75 pyrrolidinecarboxamide (m, 4H) 7-10(3R)-1-(3-chlorophenyl)- 373 1H NMR (500 MHz, CHLOROFORM-d) Shift 7.67(d, J = 1.95 N-((1R,2R,4S)-7-cyano- Hz, 1H), 7.55 (ddd, J = 0.78, 2.08,8.30 Hz, 1H), 7.29-7.33 (m, 7- 1H), 7.17 (ddd, J = 0.91, 1.98, 8.01 Hz,1H), 4.49-4.59 (m, 1H), azabicyclo[2.2.1]heptan- 4.37-4.49 (m, 1H), 4.26(br s, 1H), 4.09-4.21 (m, 1H), 3.91-4.01 2-yl)-N-methyl-5-oxo-3- (m,1H), 3.59 (br s, 1H), 3.09 (br s, 3H), 2.82-2.93 (m, 2H),pyrrolidinecarboxamide 2.24-2.38 (m, 1H), 2.07-2.16 (m, 1H), 1.91-2.02(m, 1H), 1.65- 1.73 (m, 2H) 7-11 (3S)-N-((1R,2R,4S)-7- 393 1H NMR (500MHz, CHLOROFORM-d) Shift 6.69 (t, J = 1.69 cyano-7- Hz, 1H), 6.44 (d, J= 1.69 Hz, 2H), 4.48-4.54 (m, 1H), 4.46 (br s, azabicyclo[2.2.1]heptan-1H), 4.08-4.19 (m, 1H), 3.35-3.56 (m, 4H), 3.10 (br s, 3H), 2.23-2-yl)-1-(3,5- 2.35 (m, 2H), 2.07 (s, 2H), 1.94 (br s, 1H), 1.52-1.74 (m,4H) dichlorophenyl)-N- methyl-3- pyrrolidinecarboxamide 7-12(3S)-N-((1R,2R,4S)-7- 419 1H NMR (600 MHz, DMSO-d6) Shift 8.25 (d, J =7.72 Hz, 1H), cyano-7- 7.11 (d, J = 7.81 Hz, 1H), 4.42 (br s, 1H), 4.28(br s, 1H), 4.20 (br azabicyclo[2.2.1]heptan- s, 1H), 3.87-3.95 (m, 1H),3.85 (br s, 1H), 3.75-3.82 (m, 2H), 2-yl)-1-(3-cyano-6- 3.60 (br t, J =6.86 Hz, 1H), 3.07 (br s, 2H), 2.29 (qd, J = 6.33, (trifluoromethyl)-2-12.34 Hz, 1H), 2.06 (br s, 2H), 1.61-1.80 (m, 4H) pyridinyl)-N-methyl-3-pyrrolidinecarboxamide 7-13-2 N-((1R,2R,4S)-7-cyano- m/z ¹H NMR(400 MHz,DMSO-d₆): δ ppm 7.21 (t, J = 2.5 Hz, 1 H), 7- (ESI): 6.93 (dd, J = 3.5,2.4 Hz, 1 H), 4.41 (m, 1 H), 4.20-4.25 (m, 2 H),azabicyclo[2.2.1]heptan- 429.1 3.50-3.65 (m, 4 H), 3.04 (m, 3 H),1.83-2.17 (m, 3 H), 1.73-1.67 2-yl)-N-methyl-1-(2,3,5- (M + H)+. (m, 6H). trichlorophenyl)-L- prolinamide 7-13-1 N-((1R,2R,4S)-7-cyano- m/z ¹HNMR(400 MHz, DMSO-d₆): δ ppm 7.21 (t, J = 2.5 Hz, 1 H), 7- (ESI): 6.93(dd, J = 3.5, 2.4 Hz, 1 H), 4.41 (m, 1 H), 4.20-4.25 (m, 2 H),azabicyclo[2.2.1]heptan- 429.1 3.50-3.65 (m, 4 H), 3.04 (m, 3 H),1.83-2.17 (m, 3 H), 1.73-1.67 2-yl)-N-methyl-1-(2,3,5- (M + H)+. (m, 6H). trichlorophenyl)-D- prolinamide 7-15 1-((1R,2R,4S)-7-cyano- [M + 1]7- 381.2 azabicyclo[2.2.1]heptan- 2-yl)-3-(2-(2,5-dichlorophenyl)ethyl)- 1,3-dimethylurea 7-16 1-(2-(2-bromo-5- [M + 1]chlorophenyl)ethyl)-3- 425.3 ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan- 2-yl)-1,3-dimethylurea 7-172-chloro-N-((1R,2R,4S)- 432.2 1H NMR (500 MHz, DMSO-d6) δ ppm 0.83-0.87(m, 1 H) 7-cyano-7- 1.17 (br t, J = 7.14 Hz, 1 H), 1.21-1.30 (m, 3 H)1.73 azabicyclo[2.2.1]heptan- (br d, J = 10.77 Hz, 3 H) 1.77-1.90 (m, 19H) 1.96-2.05 2-yl)-4-(6-(1- (m, 1 H) 2.14-2.23 (m, 2 H) 2.83cyanocyclopropyl)-2- (s, 6 H) 3.02-3.07 (m, 1 H) 3.31 (s, 5 H) 4.17 (brs, 1 H) 4.25 pyridinyl)-N- (br t, J = 4.28 Hz, 2 H) 4.48 (br s, 4 H)triethylbenzamide 7.51 (d, J = 8.04 Hz, 2 H) 7.57 (d, J = 7.66 Hz, 3 H)7.95-8.03 (m, 5 H) 8.10-8.24 (m, 5 H) 7-18 N-((1R,2R,4S)-7-cyano- 408.01H NMR (500 MHz, DMSO-d6) δ ppm 1.03 (d, J = 6.75 Hz, 6 H) 7- 1.24 (brs, 1 H) 1.69-1.89 (m, 5 H) azabicyclo[2.2.1]heptan- 2.15 (dt, J = 13.20,6.57 Hz, 2 H) 2.94 (s, 3 H) 3.32 (s, 3 H) 3.85- 2-yl)-N-methyl-3-(2-3.92 (m, 5 H) 4.20 (t, J = 4.67 Hz, 1 H) methylpropoxy)-4-(1- 4.24-4.33(m, 1 H) 4.41 (br s, 1 H) 7.02 (dd, J = 7.85, 1.36 methyl-1H-pyrazol-4-Hz, 1 H) 7.06 (d, J = 1.17 Hz, 1 H) 7.63 yl)benzamide (d, J = 7.79 Hz, 1H) 7.95 (s, 1 H) 8.12 (s, 1 H) 9-1 N-((1R,2R,4S)-7-cyano- 393.0 1H NMR(500 MHz, DMSO-d6) δ 1.60-1.75 (m, 3H), 1.79-1.92 7- (m, 2H), 2.24 (brd, J = 3.50 Hz, 1H), 2.85 (s, 3H), 3.81 (s, 1H),azabicyclo[2.2.1]heptan- 3.94 (s, 3H), 4.19 (t, J = 4.80 Hz, 1H), 4.28(t, J = 4.54 Hz, 1H), 2-yl)-2-methyl-4-(1- 4.36 (br dd, J = 10.96, 5.13Hz, 1H), 7.55 (s, 1H), 7.80 (s, 1H), methyl-1H-pyrazol-4- 7.89 (d, J =8.04 Hz, 1H), 8.13 (d, J = 8.04 Hz, 1H), 8.34 (s, 1H),yl))-1,3-benzothiazole-7- 8.67 (s, 1H), 8.79 (d, J = 5.84 Hz, 1H)carboxamide 9-2 N-((1R,2R,4S)-7-cyano- 474.0 1H NMR (500 MHz, DMSO-d6) δppm 0.99-1.11 (m, 8 H) 7- 1.25 (dd, J = 12.65, 4.61 Hz, 1 H) 1.44-azabicyclo[2.2.1]heptan- 1.54 (m, 3 H) 1.67-1.74 (m, 1 H) 2.11-2.19 (m,2 H) 3.32 2-yl)-5-(2- (s, 6 H) 3.81 (s, 7 H) 3.84-3.92 (m, 9 H)methylpropoxy)-2,4- 4.08 (t, J = 4.93 Hz, 1 H) 4.20 (t, J = 4.35 Hz, 1H) 4.29 (br d, bis(1-methyl-1H- J = 5.97 Hz, 1 H) 6.94 (s, 1 H) 7.56 (s,2 H) 7.61 pyrazol-4-yl)benzamide (s, 1 H) 7.68 (s, 1 H) 7.75 (s, 1 H)7.80 (s, 2 H) 7.99 (s, 1 H) 8.16 (s, 1 H) 8.48 (d, J = 6.88 Hz, 1 H) 9-32-chloro-N-((1R,2R,4S)- 428.0 1H NMR (500 MHz, DMSO-16) δ ppm 1.02 (d, J= 6.75 Hz, 6 H) 7-cyano-7- 1.05-1.10 (m, 2 H)1.21-1.29 (m, 1 H)azabicyclo[2.2.1]heptan- 1.39 (dd, J = 12.85, 4.02 Hz, 1 H) 1.57-1.63(m, 1 H) 2-yl)-5-(2- 1.67-1.75 (m, 1 H) 1.77-1.85 (m, 1 H)methylpropoxy)-4-(1- 1.98-2.04 (m, 1 H) 2.12-2.25 (m, 2 H) 3.31 (s, 4 H)3.85- methyl-1H-pyrazol-4- 3.92 (m, 6 H) 4.15 (t, J = 4.93 Hz, 1 H)yl)benzamide 4.23-4.28 (m, 2 H) 7.07 (s, 1 H) 7.71 (s, 1 H) 8.00 (s, 1H) 8.18 (s, 1H) 8.71 (d, J = 5.71 Hz, 1 H) 9-4 3-butoxy-N- 394.0 1H NMR(500 MHz, DMSO-d6) δ ppm 0.97 (t, J = 7.40 Hz, 3 H)((1R,2R,4S)-7-cyano-7- 1.46-1.53 (m, 2 H) 1.57 (dd,azabicyclo[2.2.1]heptan- J = 12.72, 4.54 Hz, 1 H) 1.65-1.72 (m, 2 H)1.79-1.89 (m, 4 H) 2-yl)-4-(1-methyl-1H- 2.18-2.24 (m, 1 H) 3.32 (s, 8H) pyrazol-4-yl)benzamide 3.88 (s, 3 H) 4.11-4.18 (m, 3 H) 4.24-4.30 (m,2 H) 7.46 (d, J = 1.43 Hz, 1 H) 7.48 (dd, J = 8.04, 1.69 Hz, 1 H) 7.69(d, J = 8.04 Hz, 1 H) 7.98 (s, 1 H) 8.15 (s, 1 H) 8.50 (d, J = 5.71 Hz,1 H) 9-5 N-((1R,2R,4S)-7-cyano- 406.0 1H NMR (500 MHz, CHLOROFORM-d) δppm 0.90 (t, J = 6.94 7- Hz, 2 H) 1.10 (d, J = 6.75 Hz, 1 H)azabicyclo[2.2.1]heptan- 1.18 (dd, J = 13.04, 3.96 Hz, 3 H) 1.23-1.34(m, 4 H) 1.62-1.68 2-yl)-3- (m, 3 H) 1.90-2.12 (m, 23 H) 2.16-(cyclobutylmethoxy)-4- 2.26 (m, 7 H) 2.52-2.60 (m, 3 H) 2.91 (dt, J =14.89, 7.54 Hz, 3 (1-methyl-1H-pyrazol-4- H) 3.96 (s, 10 H) 4.09-4.14(m, 10 yl)benzamide H) 4.47-4.53 (m, 7 H) 6.18 (br d, J = 4.41 Hz, 3 H)7.17-7.27 (m, 4 H) 7.47 (d, J = 1.43 Hz, 3 H) 7.56 (d, J = 7.91 Hz, 3 H)7.92 (d, J = 8.82 Hz, 6 H) 9-6 N-((1R,2R,4S)-7-cyano- 394.0 1H NMR (500MHz, CHLOROFORM-d) δ ppm 1.10 (d, J = 6.62 7- Hz, 22 H) 1.15-1.21 (m, 6H) 1.28 azabicyclo[2.2.1]heptan- (br dd, J = 6.10, 1.95 Hz, 2 H)1.60-1.66 (m, 5 H) 1.92-1.97 (m, 2-yl)-3-(2- 6 H) 2.08-2.12 (m, 3 H)2.23 (dt, methylpropoxy)-4-(1- J = 13.33, 6.63 Hz, 3 H) 2.56-2.59 (m, 2H) 3.92-3.98 (m, 18 methyl-1H-pyrazol-4- H) 4.12 (t, J = 4.87 Hz, 3 H)4.48-4.52 yl)benzamide (m, 7 H) 6.12 (br d, J = 3.89 Hz, 3 H) 7.20 (dd,J = 7.98, 1.62 Hz, 3 H) 7.48 (d, J = 1.43 Hz, 3 H) 7.56 (d, J = 7.91 Hz,3 H) 7.94 (d, J = 6.49 Hz, 7 H) 12-3 6-(5-azaspiro[2.5]octan- [M + 1]5-yl)-N-((1R,2R,4S)-7- 353.3 cyano-7- azabicyclo[2.2.1]heptan- 2-yl)-4-pyrimidinecarboxamide 12-4 N-((1R,2R,4S)-7-cyano- [M + 1] 7- 419.3azabicyclo[2.2.1]heptan- 2-yl)-6-(2-methyl-2- phenyl-4-morpholinyl)- 4-pyrimidinecarboxamide 12-5 6-(2-(4-chlorophenyl)-2- [M + 1]methyl-4-morpholinyl)- 453.3 N-((1R,2R,4S)-7-cyano- 7azabicyclo[2.2.1]heptan- 2-yl)-4- pyrimidinecarboxamide 12-6 6-(((1-(4-[M + 1] bromophenyl)cyclo- 481.2 propyl)methyl)(methyl)amino)-N-((1R,2R,4S)-7-cyano- 7- azabicyclo[2.2.1]heptan- 2-yl)-4-pyrimidinecarboxamide 12-7 2-chloro-N-(8-cyano-8- [M + 1]azabicyclo[2.2.1]octan- 370.3 2-yl)-4-(4-methyl-1H-pyrazol-1-yl)benzamide 12-8 3-(6-chloro-2,3-dihydro- [M + 1]1H-indol-1-yl)-N- 345.3 ((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2 -yl)propanamide 12-9 (2E)-N-((1R,2R,4S)-7- [M + 1] cyano-7- 364.2azabicyclo[2.2.1]heptan- 2-yl)-4-(2,5- dichlorophenyl)-2-methyl-2-butenamide 12-10 N((1R,2R,4S)-7-cyano- 352.2 7 -azabicyclo[2.2.1]heptan- 2-yl)-4-(2,5- dichlorophenyl)butanamide 12-11N-((1R,2R,4S)-7-cyano- 378. 1 7 - azabicyclo[2.2.1]heptan- 2-yl)-3-(2,5-dichlorophenyl)cyclopentane- carboxamide 12-12 N-((1R,2R,4S)-7-cyano-[M + 1] 7- 352.3 azabicyclo[2.2.1]heptan- 2-yl)-3-(4-fluorophenoxy)benzamide 12-13 N-((1R,2R,4S)-7-cyano- [M + 1] 7- 350.3azabicyclo[2.2.1]heptan- 2-yl)-3-(4- fluorobenzyl)benzamide 12-143-(4-chlorophenoxy)-N- [M + 1] ((1R,2R,4S)-7-cyano-7- 368.2azabicyclo[2.2.1]heptan- 2-yl)benzamide 12-15 N-((1R,2R,4S)-7-cyano-[M + 1] 7- 364.2 azabicyclo[2.2.1]heptan- 2-yl)-2-(2,5-dichlorobenzyl)cyclo- propanecarboxamide 12-16 N-((1R,2R,4S)-7-cyano-[M + 1] 7- 359.3 azabicyclo[2.2.1]heptan- 2-yl)-3-(4-cyanophenoxy)benzamide 12-17 N-(1R,2R,4S)-7-cyano- [M + 1] 7- 332.3azabicyclo[2.2.1]heptan- 2-yl)dibenzo[b,d]furan- 3-carboxamide 12-18(2E)-3-(5-chloro-1-ethyl- [M + 1] 1H-pyrrole[2,3- 570.2b]pyridin-3-yl)-N- ((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)-2-propenamide 12-19 2-(3-bromo-2- [M + 1] cyanophenoxy)-N- 375.1((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan- 2-yl)acetamide 12-20N-(2-((1R,2R,4S)-7- [M + 1] cyano-7- 359.3 azabicyclo[2.2.1]heptan-2-yl)amino)-2-oxoethyl)- 4,5,6,7-tetrahydro-1- benzothiophene-2-carboxamide 12-21 (3E)-N-((1R,2R,4S)-7- [M + 1] cyano-7- 380.3azabicyclo[2.2.1]heptan- 2-yl)-4-(2,5- dichlorophenyl)-2-methoxy-3-butenamide 12-22 (3E)-N-(1R,2R,4S)-7- [M + 1] cyano-7- 364.2azabicyclo[2.2.1]heptan- 2-yl)-4-(2,5- methyl-3-butenamide 12-232′,5′-dichloro-N- [M + 1] ((1R,2R,4S)-7-cyano-7- 386.3azabicyclo[2.2.1]heptan- 2-yl)[biphenyl]-3- carboxamide 12-24(3E)-4-(3-chlorophenyl)- [M + 1] N-((1R,2R,4S)-7-cyano- 316.2 7-azabicyclo[2.2.1]heptan- 2-yl)-3-butenamide 12-25(2E)-3-(5-chloro-1-ethyl- [M + 1] 1H-indol-3-yl)-N- 383.3((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan- 2-yl)-2-methyl-2-propenamide 12-26 (3E)-N-((1R,2R,4S)-7- [M + 1] cyano-7- 350.2azabicyclo[2.2.1]heptan- 2-yl)-4-(2,5- dichlorophenyl)-3- butenamide12-27 N-((1R,2R,4S)-7-cyano- [M + 1] 7- 335.3 azabicyclo[2.2.1]heptan-2-yl)-2,3,4,9-tetrahydro- 1H-carbazole-3- carboxamide 12-28(2E)-3-(5-chloro-1- [M + 1] benzothiophen-3-yl)-N- 372.1((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan- 2-yl)-2-methyl-2-propenamide 12-29 3′-bromo-N- [M + 1] ((1R,2R,4S)-7-cyano-7- 396.1azabicyclo[2.2.1]heptan- 2-yl)[biphenyl]-3- carboxamide 12-30(2E)-3-(5-chloro-1H- [M + 1] indazol-3-yl)-N- 356.3((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan- 2-yl)-2-methyl-2-propenamide 13-21 N-((1R,2R,4S)-7-cyano- 373.2 1H NMR (CHLOROFORM-d) δ;8.69 (d, J = 4.9 Hz, 1H), 8.60 7- (s, 1H), 8.55-8.64 (m, 1H), 8.25-8.34(m, 1H), 7.73 (d, J = 8.4 Hz, azabicyclo[2.2.1]heptan- 1H), 7.11 (d, J =4.8 Hz, 1H), 6.94 (s, 1H), 6.90-6.98 (m, 1H), 2-yl)-6-(4-methyl-2- 4.56(br dd, J = 9.7, 5.0 Hz, 1H), 4.45-4.51 (m, 1H), 4.14 (t, J = 5.1pyrimidinyl)-1H-indole- Hz, 1H), 2.66 (s, 1H), 2.64-2.68 (m, 1H),2.52-2.63 (m, 1H), 2-carboxamide 2.12 (br dd, J = 4.3, 2.1 Hz, 1H),1.92-2.03 (m, 3H), 1.70 (br s, 2H) 13-22 5-(3-chlorophenyl)-N- 341.8 1HNMR (600 MHz, DMSO-d6) Shift 8.57 (br d, J = 5.22 Hz,((1R,2R,4S)-7-cyano-7- 1H), 7.98 (t, J = 1.71 Hz, 1H), 7.87 (td, J =1.22, 7.84 Hz, 1H), azabicyclo[2.2.1]heptan- 7.52 (t, J = 7.90 Hz, 1H),7.44 (d, J = 8.24 Hz, 1H), 7.21-7.29 (m, 2-yl)-2- 2H), 4.22-4.30 (m,2H), 4.18 (t, J = 4.79 Hz, 1H), 2.20-2.27 (m, furancarboxamide 1H),1.79-1.91 (m, 2H), 1.66-1.75 (m, 2H), 1.59 (dd, J = 4.28, 12.85 Hz, 1H)13-23 N-((1R,2R,4S)-7-cyano- 353 1H NMR (500 MHz, CHLOROFORM-d) Shift8.08-8.12 (m, 7- 1H), 6.42 (d, J = 5.19 Hz, 1H), 5.82-5.95 (m, 1H),4.30-4.36 (m, azabicyclo[2.2.1]heptan- 2H), 4.01-4.11 (m, 1H), 3.75-3.90(m, 2H), 3.66-3.75 (m, 1H), 2-yl)-1-(4-cyclopropyl- 3.54 (td, J = 7.77,11.06 Hz, 1H), 2.96-3.03 (m, 1H), 2.39-2.48 2-pyrimidinyl)-3- (m, 1H),2.17-2.31 (m, 2H), 1.97-2.12 (m, 3H), 1.50-1.59 (m,pyrrolidinecarboxamide 1H), 0.94-1.12 (m, 5H) 13-24N-((1R,2R,4S)-7-cyano- 379 1H NMR (500 MHz, CHLOROFORM-d) Shift 7.33 (t,J = 7.98 7- Hz, 1H), 6.94-6.99 (m, 1H), 6.76-6.78 (m, 1H), 6.71-6.74 (m,azabicyclo[2.2.1]heptan- 1H), 5.82 (br d, J = 4.41 Hz, 1H), 4.32-4.38(m, 2H), 4.07 (t, 2-yl)-1-(3- J = 5.00 Hz, 1H), 3.49-3.60 (m, 3H),3.36-3.43 (m, 1H), 3.03-3.10 (trifluoromethyl)phenyl)- (m, 1H),2.43-2.51 (m, 1H), 2.25-2.38 (m, 2H), 2.00-2.11 (m, 3- 1H), 1.87-1.98(m, 1H), 1.79-1.85 (m, 1H), 1.56 (tdd, J = 3.92, pyrrelidinecarboxamide8.63, 12.46 Hz, 1H), 1.04 (dd, J = 3.57, 13.04 Hz, 1H) 13-25N-((1R,2R,4S)-7-cyano- 379 1H NMR (500 MHz, CHLOROFORM-d) d 6.69-6.72(m, 1H), 7- 6.42-6.45 (m, 2H), 5.59-5.68 (m, 1H), 4.31-4.39 (m, 2H),4.06- azabicyclo[2.2.1]heptan- 4.10 (m, 1H), 3.44-3.52 (m, 3H),3.31-3.38 (m, 1H), 2.99-3.07 2-yl)-1-(3,5- (m, 1H), 2.45-2.54 (m, 1H),2.25-2.35 (m, 2H), 2.04-2.13 (m, dichlorophenyl)-3- 1H), 1.89-1.99 (m,1H), 1.77-1.85 (m, 1H), 1.00-1.06 (m, 1H) pyrrolidinecarboxamide 13-26N-((1R,2R,4S)-7-cyano- 380 1H NMR (500 MHz, CHLOROFORM-d) Shift 7.56 (t,J = 7.91 7- Hz, 1H), 6.92 (d, J = 7.27 Hz, 1H), 6.52 (d, J = 8.56 Hz,1H), 5.92- azabicyclo[2.2.1]heptan- 6.04 (m, 1H), 4.28-4.37 (m, 2H),4.06 (dt, J = 2.34, 4.93 Hz, 1H), 2-yl)-1-(6- 3.77-3.85 (m, 1H),3.65-3.75 (m, 2H), 3.43-3.53 (m, 1H), 2.99- (trifluoromethyl)-2- 3.07(m, 1H), 2.40-2.48 (m, 1H), 2.23-2.38 (m, 2H), 1.99-2.06 pyridinyl)-3-(m, 1H), 1.76-1.94 (m, 2H), 1.52-1.64 (m, 1H), 1.04-1.10 (m,pyrrolidinecarboxamide 1H) 13-27 2-chloro-N-((1R,2R,4S)- 428.0 1H NMR(500 MHz, DMSO-d6) δ ppm 0.86 (br t, J = 6.81 Hz, 1 7-cyano-7- H) 1.00(d, J = 6.75 Hz, 6 H) 1.24 (br s, azabicyclo[2.2.1]heptan- 1 H) 1.37 (brdd, J = 12.85, 3.76 Hz, 1 H) 1.53-1.65 (m, 1 H) 2-yl)-3-(2- 1.67-1.76(m, 1 H) 1.76-1.87 (m, 1 H) methylpropoxy)-4-(1- 1.95-2.05 (m, 1 H) 2.10(dt, J = 13.23, 6.62 Hz, 1 H) 2.16-2.27 methyl-1H-pyrazol-4- (m, 1 H)3.32 (s, 2 H) 3.45-3.59 (m, yl)benzamide 2 H) 3.89 (s, 3 H) 4.14 (t, J =4.80 Hz, 1 H) 4.20-4.31 (m, 2 H) 7.18 (d, J = 8.04 Hz, 1 H) 7.58 (d, J =8.04 Hz, 1 H) 7.90 (s, 1 H) 8.11-8.19 (m, 1 H) 8.74 (br d, J = 5.58 Hz,1 H) 13-28 2-chloro-N-((1R,2R,4S)- 428.0 1H NMR (500 MHz, DMSO-d6) δ ppm0.86-0.93 (m, 18 H) 7-cyano-7- 0.99 (d, J = 6.75 Hz, 1 H) 1.37 (dd,azabicyclo[2.2.1]heptan- J = 12.78, 3.83 Hz, 3 H) 1.53-1.66 (m, 2 H)1.67-1.77 (m, 2 H) 2-yl)-3-(2- 1.78-1.95 (m, 5 H) 2.00 (ddd,methylpropoxy)-4-(4- J = 12.75, 8.99, 3.83 Hz, 2 H) 2.10 (s, 9 H)2.16-2.27 (m, 2 H) methyl-1H-pyrozol-1- 2.81 (s, 3 H) 3.02 (s, 3 H) 3.31(s, 4 H) yl)benzamide 3.36-3.42 (m, 6 H) 4.15 (t, J = 4.87 Hz, 2 H)4.23-4.31 (m, 4 H) 7.21 (d, J = 8.17 Hz, 1 H) 7.31 (d, J = 8.30 Hz, 2 H)7.56-7.66 (m, 6 H) 7.95-7.99 (m, 3 H) 8.84 (br d, J = 5.84 Hz, 2 H)13-29 N-((1R,2R,4S)-7-cyano- 394.0 1H NMR (500 MHz, DMSO-d6) δ 0.99 (brd, J = 6.10 Hz, 6H), 7 1.52-1.64 (m, 1H), 1.64-1.77 (m, 2H), 1.77-1.91(m, 2H), 2.10 azabicyclo[2.2.1]heptan- (br s, 4H), 2.22 (br s, 1H), 3.95(br d, J = 5.19 Hz, 2H), 4.17 (br s, 2-yl)-3-(2- 1H), 4.27 (br s, 2H),7.45-7.69 (m, 3H), 7.77 (br d, J = 7.79 Hz, methylpropoxy)-4-(4- 1H),8.06 (br s, 1H), 8.51-8.74 (m, 1H) methyl-1H-pyrozol-1- yl)benzamide13-30 N-((1R,2R,4S)-7-cyano- 387.0 1H NMR (500 MHz, DMSO-d6) δ ppm1.58-1.66 (m, 2H) 7- 1.67-1.76 (m, 5 H) 1.79-1.93 (m, 5 H)azabicyclo[2.2.1]heptan- 2.22 (br s, 1 H) 2.56-2.76 (m, 28 H) 2.80 (brs, 1 H) 3.30-3.34 2-yl)-7-methyl-1-(6- (m, 32 H) 4.17 (br s, 4 H) 4.26(br s, methyl-2-pyridinyl)-1H- 8H) 7.39 (br s, 2 H) 7.55 (br s, 2 H)7.99 (br s, 2 H) 8.06 (br s, 3 indazole-5-carboxamide H) 8.22 (br s, 2H) 8.61 (br s, 1 H) 9.35 (br s, 1 H) 15-2 N-((1R,2R,4S)-7-cyano- 409.21H NMR (DMSO-d6) δ: 9.17 (d, J = 8.9 Hz, 1H), 8.75 (d, J = 6.1 7- Hz,1H), 8.69 (s, 1H), 8.59 (d, J = 8.9 Hz, 1H), 8.50 (s, 1H), 8.29azabicyclo[2.2.1]heptan- (d, J = 9.0 Hz, 1H), 8.15 (ddd, J = 8.7, 1.6,1.4 Hz, 2H), 8.05 (d, 2-yl)-1-(2-quinolinyl)- J = 8.4 Hz, 1H), 7.85(ddd, J = 8.3, 7.0, 1.4 Hz, 1H), 7.62 (t, J = 7.6 1H-indazole-5- Hz,1H), 4.37 (br dd, J = 11.1, 4.9 Hz, 1H), 4.29 (t, J = 4.5 Hz,carboxamide 1H), 4.20 (t, J = 4.9 Hz, 1H), 2.22-2.28 (m, 1H), 1.92-1.98(m, 1H), 1.81-1.89 (m, 1H), 1.68-1.76 (m, 2H), 1.61 (dd, J = 12.8, 4.8Hz, 1H) 15-3 N-((1R,2R,4S)-7-cyano, 423.2 1H NMR (DMSO-d6) δ: 8.65-8.78(m, 4H), 8.48 (s, 1H), 8.22 (t, 7- J = 8.0 Hz, 1H), 8.18 (dd, J = 8.9,1.6 Hz, 1H), 8.05-8.12 (m, 1H), azabicyclo[2.2.1]heptan- 7.98 (d, J =8.1 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.18-7.30 (m,2-yl)-1-(6-(1H-imidazol- 1H), 4.36 (br dd, J = 10.9, 4.9 Hz, 1H), 4.28(t, J = 4.6 Hz, 1H), 1-yl)-2-pyridinyl)-1H- 4.19 (t, J = 4.9 Hz, 1H),2.20-2.28 (m, 1H), 1.89-1.98 (m, 1H), indazole-5-carboxamide 1.80-1.88(m, 1H), 1.66-1.76 (m, 2H), 1.55-1.65 (m, 1H) 15-4N-((1R,2R,4S)-7-cyano- 435.2 1H NMR (DMSO-d6) δ: 8.92 (d, J = 8.9 Hz,1H), 8.72 (d, J = 6.1 7- Hz, 1H), 8.65 (s, 1H), 8.49 (d, J = 0.9 Hz,1H), 8.11-8.23 (m, 4H), azabicyclo[2.2.1]heptan- 8.01 (d, J = 8.1 Hz,1H), 7.94 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 7.6 Hz, 2-yl)-1-(6-phenyl-2-2H), 7.49-7.57 (m, 1H), 4.33-4.40 (m, 1H), 4.28 (t, J = 4.6 Hz,pyridinyl)-1H-indazole- 1H), 4.19 (t, J = 4.9 Hz, 1H), 2.20-2.28 (m,1H), 1.91-1.98 (m, 5-carboxamide 1H), 1.80-1.88 (m, 1H), 1.67-1.76 (m,2H), 1.61 (dd, J = 12.7, 4.7 Hz, 1H) 15-5 N-((1R,2R,4S)-7-cyano- 424.01H NMR (DMSO-d6) δ: 8.80 (d, J = 8.9 Hz, 1H), 8.76 (d, J = 2.3 7- Hz,1H), 8.73 (d, J = 6.2 Hz, 1H), 8.67 (s, 1H), 8.49 (s, 1H), 8.16-azabicyclo[2.2.1]heptan- 8.23 (m, 2H), 7.96 (d, J = 8.1 Hz, 1H), 7.92(d, J = 1.0 Hz, 1H), 2-yl)-1-(6-(1H-pyrazol- 7.85 (d, J = 7.9 Hz, 1H),6.69-6.73 (m, 1H), 4.37 (br dd, J = 11.2, 1-yl)-2-pyridinyl)-1H- 4.9 Hz,1H), 4.28 (t, J = 4.5 Hz, 1H), 4.14-4.24 (m, 1H), 2.21-2.28indazole-5-carboxamide (m, 1H), 1.80-1.97 (m, 2H), 1.67-1.76 (m, 2H),1.60 (dd, J = 12.7, 4.6 Hz, 1H) 15-6 N-((1R,2R,4S)-7-cyano- 1H NMR(DMSO-d6) δ: 8.78 (d, J = 8.9 Hz, 1H), 8.70 (d, J = 6.1 7- Hz, 1H), 8.63(s, 1H), 8.46 (s, 1H), 8.10 (dd, J = 8.9, 1.3 Hz, 1H),azabicyclo[2.2.1]heptan- 8.04 (t, J = 8.0 Hz, 1H), 7.95 (d, J = 8.2 Hz,1H), 7.37 (d, J = 7.7 Hz, 2-yl)-1-(6-((1,1- 1H), 4.35 (br dd, J = 10.9,4.9 Hz, 1H), 4.23-4.30 (m, 1H), 4.18 (t, difluroethyl)-2- J = 4.9 Hz,1H), 2.19-2.28 (m, 1H), 1.79-2.02 (m, 6H), 1.68-1.72pyridinyl)-1H-indazole- (m, 1H), 1.60 (dd, J = 12.7, 4.7 Hz, 1H)5-carboxamide 15-7 N-((1R,2R,4S)-7-cyano- 425.2 1H NMR (CHLOROFORM-d) δ:8.65 (6, J = 8.8 Hz, 1H), 8.32 7- (s, 1H), 8.32 (s, 1H), 7.88-7.96 (m,3H), 6.86 (dd, J = 7.8, 0.8 Hz, azabicyclo[2.2.1]heptan- 1H), 6.17 (brs, 1H), 4.51-4.61 (m, 2H), 4.15 (t, J = 5.1 Hz, 1H), 2-yl)-1-(6-2.58-2.65 (m, 1H), 2.10-2.17 (m, 1H), 1.96-2.03 (m, 2H), 1.64-(difluoromethoxy)-2- 1.70 (m, 1H), 1.28 (s, 1H), 1.20 (dd, J = 13.0, 4.4Hz, 1H) pyridinyl)-1H-indazole- 5-carboxamide 15-8N-((1R,2R,4S)-7-cyano- 425.2 1H NMR (CHLOROFORM-d) δ: 8.91 (d, J = 9.0Hz, 1H), 8.32 7- (d, J = 0.8 Hz, 1H), 8.30 (d, J = 0.9 Hz, 1H), 8.23(dd, J = 8.4, 0.8 azabicyclo[2.2.1]heptan- Hz, 1H), 8.03 (t, J = 8.0 Hz,1H), 7.93 (dd, J = 8.9, 1.8 Hz, 1H), 2-yl)-1-(6- 7.54 (d, J = 7.5 Hz,1H), 6.76 (t, J = 55.5 Hz, 1H), 6.18 (br d, J = 6.0 (difluoromethyl)-2-Hz, 1H), 4.52-4.61 (m, 2H), 4.15 (t, J = 5.1 Hz, 1H), 2.58-2.65pyridinyl)-1H-Indazole- (m, 1H), 2.09-2.18 (m, 1H), 1.97-2.03 (m, 2H),1.62-1.70 (m, 5-carboxamide 1H), 1.20 (dd, J = 12.9. 4.5 Hz, 1H) 15-91-([2,2′-bipyridin]-6-yl)- 436.2 1H NMR (DMSO-d6) δ: 8.91 (br d, J = 8.8Hz, 1H), 8.77 (br d, N-((1R,2R,4S)-7-cyano- J = 3.8 Hz, 1H), 8.73 (br d,J = 6.1 Hz, 1H), 8.60-8.69 (m, 1H), 7- 8.44-8.53 (m, 2H), 8.33 (d, J =7.7 Hz, 1H), 8.13-8.23 (m, 2H), azabicyclo[2.2.1]heptan- 8.04-8.13 (m,2H), 7.54 (t, J = 6.4 Hz, 1H), 4.32-4.43 (m, 1H), 2-yl)-1H-indazole-5-4.29 (t, J = 4.6 Hz, 1H), 4.19 (t, J = 4.9 Hz, 1H), 2.19-2.30 (m, 1H),carboxamide 1.90-2.00 (m, 1H), 1.79-1.89 (m, 1H), 1.67-1.77 (m, 2H),1.62 (dd, J = 12.8, 4.7 Hz, 1H) 15-10 3-(3-chlorophenyl)-N- 357 1H NMR(500 MHz, METHANOL-d4) d 7.09-7.19 (m, 1H), ((1R,2R,4S)-7-cyano-7-6.59-6.71 (m, 2H), 6.50-6.59 (m, 1H), 4.19-4.35 (m, 2H), 4.06-azabicyclo[2.2.1]heptan- 4.16 (m, 1H), 3.70-3.81 (m, 1H), 3.50-3.62 (m,2H), 3.25-3.30 2-yl)-3- (m, 1H), 2.19-2.36 (m, 2H), 1.69-2.01 (m, 4H),1.42-1.52 (m, azabicyclo[3.1.0]hexane- 2H), 1.26-1.39 (m, 1H), 0.96-1.00(m, 1H) 1-carboxamide 15-11 N-((1R,2R,4S)-7-cyano- 376 1H NMR (500 MHz,CHLOROFORM-d) Shift 7.94 (d, J = 2.59 7- Hz, 1H), 7.66 (d, J = 1.69 Hz,2H), 7.39 (t, J = 1.75 Hz, 1H), 7.05 azabicyclo[2.2.1]heptan- (d, J =2.59 Hz, 1H), 6.93-6.97 (m, 1H), 4.45-4.56 (m, 2H), 4.14 2-yl)-1-(3,5-(t, J = 5.00 Hz, 1H), 2.51-2.63 (m, 1H), 2.06-2.16 (m, 1H), 1.90-dichlorophenyl)-1H- 2.04 (m, 2H), 1.72 (ddd, J = 4.54, 8.47, 12.55 Hz,1H), 1.24-1.33 pyrazole-3-carboxamide (m, 1H) 15-12-2 (1S,4R,5S)-N- m/z¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.40 (d, J = 5.7 Hz, 1 H),((1R,2R,4S)-7-cyano-7- (ESI): 6.61-7.42 (m, 3 H), 3.94-4.37 (m, 3 H),3.75 (t, J = 9.8 Hz, 1 azabicyclo[2.2.1]heptan- 390.0(M + H), 3.42-3.55(m, 1 H), 2.96 (dd, J = 10.3, 8.8 Hz, 1 H), 2.19- 2-yl)-2-(3,5- H)+.2.38 (m, 1 H), 1.92-2.07 (m, 1 H), 1.78-1.92 (m, 1 H), 1.56-dichlorophenyl)-2- 1.72 (m, 2 H), 1.17-1.37 (m, 3 H), 0.85 (t, J = 6.5Hz, 1 H), azabicyclo[3.1.0]hexane- 0.56-0.70 (m, 1 H). 4-carboxamide15-12-1 (1S,4S,5S)-N- m/z ¹H NMR(400 MHz, DMSO-d₆): δ ppm 8.40 (d, J =5.7 Hz, 1 H), ((1R,2R,4S)-7-cyano-7- (ESI): 6.61-7.42 (m, 3 H),3.94-4.37 (m, 3 H), 3.75 (t, J = 9.8 Hz, 1 azabicyclo[2.2.1]heptan-390.0(M + H), 3.42-3.55 (m, 1 H), 2.96 (dd, J = 10.3, 8.8 Hz, 1 H),2.19- 2-yl)-2-(3,5- H)+. 2.38 (m, 1 H), 1.92-2.07 (m, 1 H), 1.78-1.92(m, 1 H), 1.56- dichlorophenyl)-2- 1.72 (m, 2 H), 1.47 (m, 1 H),1.17-1.37 (m, 2 H), 0.85 (t, J = 6.5 azabicyclo[3.1.0]hexane- Hz, 1 H),0.56 -0.70 (m, 1 H). 4-carboxamide 15-14 N-((1S,2R,4S)-7-cyano- m/z ¹HNMR(400 MHz, DMSO-d₆): δ ppm 8.04 (dd, J = 6.2, 1.9 Hz, 7- (ESI): 1H),6.23-7.34 (m, 3 H), 3.90-4.37 (m, 3 H), 3.40-3.66 (m,azabicyclo[2.2.1]heptan- 407.1, 3 H), 2.06-2.28 (m, 2 H), 1.80-2.07 (m,2 H), 1.40-1.81 (m, 2-yl)-1-(3,5- 409.1 9 H), 1.21 (dd, J = 12.7, 4.6Hz, 1 H). dichlorophenyl)-4- (M + H)⁺. azepanecarboxamide 15-156-chloro-N-((1R,2R,4S)- 417.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.33-1.47(m, 1 H) 7-cyano-7- 1.61 (ddd, J = 12.03, 9.15, 4.05 Hz, 1 H)azabicyclo[2.2.1]heptan- 1.72-1.78 (m, 1 H) 1.80-1.87 (m, 1 H) 2.04(ddd, J = 12.96, 2-yl)-1-(6-cyano-2- 9.07, 4.13 Hz, 1 H) 2.21-2.29 (m, 1H) pyridinyl)-1H-indazole- 3.32-3.38 (m, 75 H) 4.12-4.24 (m, 1 H)4.26-4.37 (m, 2 H) 5-carboxamide 8.01 (d, J = 7.66 Hz, 1 H) 8.08-8.20(m, 1 H) 8.27 (t, J = 8.17 Hz, 1 H) 8.34 (d, J = 8.52 Hz, 1 H) 8.64 (s,1 H) 8.73 (d, J = 0.62 Hz, 1 H) 8.89 (br d, J = 5.76 Hz, 1 H) 15-166-chloro-N-((1R,2R,4S)- 418.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.40 (dd,J = 12.69, 4.28 7-cyano-7- Hz, 1 H) 1.54-1.67 (m, 1 H) 1.67-1.91azabicyclo[2.2.1]heptan- (m, 2 H) 2.04 (ddd, J = 12.96, 9.07, 4.28 Hz, 1H) 2.20-2.30 2-yl)-1-(4-cyano-2- (m, 1 H) 3.31-3.39 (m, 129 H) 4.11-4.21pyridinyl)-1H-indazole- (m, 1 H) 4.25-4.35 (m, 2 H) 8.08 (s, 1 H)8.62-8.70 (m, 5-carboxamide 1 H) 8.84 (d, J = 0.62 Hz, 1 H) 8.85-8.91(m, 2 H) 16-3 N-((1R,2R,4S)-7-cyano- 329.0 1H NMR (DMSO-d6, 600 MHz)Shift 9.16 (d, 1H, J = 6.5 Hz), 7- 8.23 (s, 1H), 8.13 (s, 1H), 7.89 (d,1H, J = 0.8 Hz), 4.3-4.3 (m, azabicyclo[2.2.1]heptan- 1H), 4.21 (t, 1H,J = 4.7 Hz), 4.1-4.2 (m, 1H), 3.87 (s, 3H), 2.1- 2-yl)-5-(1-methyl-1H-2.2 (m, 1H), 1.8-1.9 (m, 1H), 1.6-1.8 (m, 4H) pyrazol-4-yl)-1,3-thiazole-2-carboxamide 16-4 N-((1R,2R,4S)-7-cyano- 350.0 1H NMR (500MHz, CHLOROFORM-d) Shift 8.34 (t, J = 1.43 7- Hz, 1H), 8.22 (s, 1H),8.14 (d, J = 7.81 Hz, 1H), 7.79 (td, J = 1.31, azabicyclo[2.2.1]heptan-7.75 Hz, 1H), 7.64 (t, J = 7.85 Hz, 1H), 7.40 (br d, J = 5.84 Hz,2-yl)-2-(3-cyanophenyl)- 1H), 4.50-4.60 (m, 1H), 4.47 (t, J = 4.22 Hz,1H), 4.12-4.20 (m, 1,3-thiazole-4- 1H), 2.60 (dddd, J = 3.11, 5.19,11.11, 13.02 Hz, 1H), 1.94-2.17 carboxamide (m, 3H), 1.71-1.80 (m, 1H),1.25-1.38 (m, 1H) 16-5 N-((1R,2R,4S)-7-cyano- 365.1 1H NMR (500 MHz,CHLOROFORM-d) Shift 8.12 (s, 1H), 7- 7.72-7.75 (m, 1H), 7.67 (t, J =1.82 Hz, 1H), 7.46 (br d, J = 5.84 azabicyclo[2.2.1]heptan- Hz, 1H),7.38 (t, J = 7.72 Hz, 1H), 7.18 (td, J = 1.18, 7.75 Hz, 1H), 2-yl)-2-(3-4.47-4.56 (m, 2H), 4.14 (t, J = 5.06 Hz, 1H), 2.58 (dddd, J = 3.05,cyclopropylphenyl)-1,3- 5.22, 11.05, 12.99 Hz, 1H), 1.94-2.15 (m, 4H),1.71 (ddd, thiazole-4-carboxamide J = 4.41, 8.60, 12.55 Hz, 1H),1.25-1.33 (m, 1H), 1.04-1.10 (m, 2H), 0.76-0.86 (m, 2H) 20-1N-((1R,2R,4S)-7-cyano- 373.0 1H NMR (DMSO-d6) δ: 8.83 (d, J = 5.1 Hz,1H), 8.35 (br t, J = 6.6 7- Hz, 2H), 8.23 (br d, J = 2.8 Hz, 1H),8.14-8.21 (m, 1H), 7.34 (d, azabicyclo[2.2.1]heptan- J = 5.0 Hz, 1H),7.28 (t, J = 7.7 Hz, 1H), 4.31-4.40 (m, 1H), 4.27 2-yl)-7-(4-methyl-2-(s, 1H), 4.16 (s, 1H), 4.03-4.12 (m, 1H), 2.65 (s, 3H), 2.17-2.30pyrimidinyl)-1H-indole- (m, 1H), 1.90-2.00 (m, 1H), 1.78-1.88 (m, 1H),1.70 (br s, 2H), 3-carboxamide 1.53 (br dd, J = 12.7, 4.7 Hz, 1H) 20-2N-((1R,2R,4S)-7-cyano- 372.0 1H NMR (DMSO-d6) δ: 11.77 (br s, 1H), 8.24(d, J = 7.9 Hz, 7- 1H), 8.20 (d, J = 2.8 Hz, 1H), 8.15 (br d, J = 5.8Hz, 1H), 7.91 (d, azabicyclo[2.2.1]heptan- J = 7.9 Hz, 1H), 7.83 (t, J =7.8 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 2-yl)-7-(6-methyl-2- 7.22-7.27(m, 2H), 4.31-4.40 (m, 1H), 4.27 (t, J = 4.4 Hz, 1H),pyridinyl)-1H-indole-3- 4.16 (t, J = 4.9 Hz, 1H), 2.70 (s, 3H),2.19-2.28 (m, 1H), 1.89- carboxamide 1.99 (m, 1H), 1.79-1.88 (m, 1H),1.65-1.74 (m, 2H), 1.53 (dd, J = 12.7, 4.7 Hz, 1H) 20-3 2′,3-dichloro-N-425.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.07 (s, 1 H) 1.24 (s, 1((1R,2R,4S)-7-cyano-7- H) 1.41 (dd, J = 12.72, 4.27 Hz, 1 H)azabicyclo[2.2.1]heptan- 1.57-1.66 (m, 1 H) 1.69-1.77 (m, 1 H) 1.82 (dt,J = 11.97, 3.78 2-yl)-3′- Hz, 1 H) 2.02 (ddd, J = 12.92, 9.06,(cyanomethyl)[biphenyl]- 4.18 Hz, 1 H) 2.18-2.27 (m, 1 H) 2.51-2.60 (m,1 H) 4.16 (t, 4-carboxamide J = 5.00 Hz, 1 H) 4.18 (s, 2 H) 4.24- 4.32(m, 2 H) 7.43 (dd, J = 7.67, 1.68 Hz, 1 H) 7.46 (dd, J = 7.86, 1.68 Hz,1 H) 7.51 (t, J = 7.67 Hz, 1 H) 7.53-7.57 (m, 2 H) 7.63 (dd, J = 7.72,1.63 Hz, 1 H) 8.89 (d, J = 6.09 Hz, 1 H) 20-4 3,3′-dichloro-N- 425.0 1HNMR (600 MHz, DMSO-d6) δ ppm 0.85 (br t, J = 7.04 Hz,((1R,2R,4S)-7-cyano-7- 1 H) 1.07 (s, 1 H) 1.24 (s, 1 H) 1.39 (dt,azabicyclo[2.2.1]heptan- J = 8.45, 4.22 Hz, 1 H) 1.55-1.65 (m, 1 H)1.68-1.77 (m, 1 H) 2-yl)-5′ 1.77-1.87 (m, 1 H) 2.01 (ddd,(cyanomethyl)[biphenyl]- J = 12.90, 8.99, 4.09 Hz, 1 H) 2.20-2.27 (m, 1H) 4.13 (s, 2 H) 4-carboxamide 4.15 (t, J = 4.95 Hz, 1 H) 4.24-4.31 (m,2 H) 7.51 (t, J = 1.68 Hz, 1 H) 7.56 (d, J = 7.90 Hz, 1 H) 7.72 (s, 1 H)7.76 (dd, J = 7.99, 1.82 Hz, 1 H) 7.82 (t, J = 1.73 Hz, 1 H) 7.90 (d, J= 1.73 Hz, 1 H) 8.84 (br d, J = 6.00 Hz, 1 H) 20-5 2′,3-dichloro-N-425.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.07 (s, 1 H) 1.24 (s, 1((1R,2R,4S)-7-cyano-7- H) 1.35-1.42 (m, 1 H) 1.55-1.64 (m,azabicyclo[2.2.1]heptan- 1 H) 1.68-1.77 (m, 1 H) 1.77-1.86 (m, 1 H) 2.01(ddd, 2-yl)-5′ J = 12.92, 8.97, 4.09 Hz, 1 H) 2.23 (br t,(cyanomethyl)[biphenyl]- J = 10.99 Hz, 1 H) 2.51-2.62 (m, 1H) 4.12-4.17(m, 3 H) 4.24- 4-carboxamide 4.32 (m, 2 H) 7.57 (d, J = 7.99 Hz, 1 H)7.66 (d, J = 8.36 Hz, 1 H) 7.73 (dd, J = 7.99, 1.73 Hz, 1 H), 7.78 (dd,J = 8.40, 2.32 Hz, 1 H) 7.85 (d, J = 1.73 Hz, 1H) 7.94 (d, J = 2.27 Hz,1 H) 8.82 (br d, J = 5.90 Hz, 1H) 20-6 3,4′-dichloro-N- 425.0 1H NMR(600 MHz, DMSO-d6) δ ppm 1.07 (s, 2 H) 1.24 (s, 1 ((1R,2R,4S)-7-cyano-7-H) 1.40 (dd, J = 12.67, 4.31 Hz, 1 H) azabicyclo[2.2.1]heptan- 1.56-1.65(m, 1 H) 1.69-1.77 (m, 1 H) 1.78-1.86 (m, 1 H) 2-yl)-3′- 2.02 (ddd, J =12.92, 9.06, 4.09 Hz, 1 H) (cyanomethyl)[biphenyl]- 2.18-2.27 (m, 1 H)4.10 (s, 2 H) 4.16 (t, J = 4.95 Hz, 1 H) 4.24- 4-carboxamide 4.32 (m, 2H) 7.42 (d, J = 2.18 Hz, 1 H) 7.45 (dd, J = 8.27, 2.27 Hz, 1 H) 7.48(dd, J = 7.86, 1.68 Hz, 1 H) 7.56 (d, J = 7.81 Hz, 1 H) 7.59 (d, J =1.63 Hz, 1H) 7.64 (d, J = 8.27 Hz, 1 H), 8.88 (br d, J = 5.99 Hz, 1H)20-7 3-chloro-N-((1R,2R,4S)- 419.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.07(s, 1 H) 1.24 (s, 1 7-cyano-7- H) 1.34-1.43 (m, 1 H) 1.56-1.66 (m,azabicyclo[2.2.1]heptan- 1 H) 1.70-1.76 (m, 1 H) 1.77 (s, 6 H) 1.82 (td,J = 7.77, 4.18 Hz, 2-yl)-3′-(2-cyano-2- 1 H) 2.02 (ddd, J = 12.92, 9.01,4.22 propanyl)[biphenyl]-4- Hz, 1 H) 2.18-2.28 (m, 1 H) 2.37-2.47 (m, 1H) 4.16 (t, J = 4.90 carboxamide Hz, 1 H) 4.24-4.32 (m, 2 H) 7.53- 7.57(m, 2 H) 7.57-7.61 (m, 1 H) 7.69 (dt, J = 7.56, 1.49 Hz, 1 H) 7.74 (dd,J = 7.90, 1.73 Hz, 1 H) 7.79 (t, J = 1.73 Hz, 1 H) 7.87 (d, J = 1.73 Hz,1 H) 8.81 (br d, J = 6.68 Hz, 1 H) 20-8 3-chloro-N-((1R,2R,4S)- 409.0 1HNMR (600 MHz, DMSO-d6) δ ppm 1.07 (s, 2 H) 1.34-1.42 7-cyano-7- (m, 1 H)1.56-1.64 (m, 1 H) 1.73 (br azabicyclo[2.2.1]heptan- d, J = 12.17 Hz, 1H) 1.81 (br dd, J = 8.49, 3.95 Hz, 1 H) 2.01 2-yl)-3′-(cyanomethyl)-(ddd, J = 12.92, 8.97, 4.09 Hz, 1 H) 2.23 5′-fluoro[biphenyl]-4- (br s,1 H) 3.15-3.19 (m, 14 H) 4.05-4.12 (m, 6 H) 4.15 (t, carboxamide J =4.86 Hz, 1 H) 4.24-4.31 (m, 1 H) 7.41 (t, J = 9.17 Hz, 1 H) 7.55 (d, J =7.99 Hz, 1 H) 7.70 (dd, J = 7.95, 1.77 Hz, 1 H) 7.76-7.86 (m, 1 H) 8.82(br d, J = 6.00 Hz, 1 H) 20-9 3-chloro-N-(1R,2R,4S)- 409.0 1H NMR (600MHz, DMSO-d6) δ ppm 1.07 (s, 2 H) 1.34-1.42 7-cyano-7- (m, 1 H)1.56-1.64 (m, 1 H) 1.73 (br azabicyclo[2.2.1]heptan- d, J = 12.17 Hz, 1H) 1.81 (br dd, J = 8.49, 3.95 Hz, 1 H) 2.01 2-yl)-3′-(cyanomethyl)-(ddd, J = 12.92, 8.97, 4.09 Hz, 1 H) 2.23 4′-fluoro[biphenyl]-4- (br s,1 H) 3.15-3.19 (m, 14 H) 4.05-4.12 (m, 6 H) 4.15 (t, carboxamide J =4.86 Hz, 1 H) 4.24-4.31 (m, 1 H) 7.41 (t, J = 9.17 Hz, 1 H) 7.55 (d, J =7.99 Hz, 1 H) 7.70 (dd, J = 7.95, 1.77 Hz, 1 H) 7.76-7.86 (m, 1 H) 8.82(br d, J = 6.00 Hz, 1 H) 20-10 3-chloro-N-((1R,2R,4S)- 409.0 1H NMR (600MHz, DMSO-d6) δ ppm 1.04-1.10 (m, 2 H) 7-cyano-7- 1.24 (s, 1 H) 1.39 (brdd, J = 12.72, 4.09 azabicyclo[2.2.1]heptan- Hz, 1 H) 1.56-1.65 (m, 1 H)1.73 (br d, J = 12.26 Hz, 1 H) 1.78- 2-yl)-3′-(cyanomethyl)- 1.86 (m, 1H) 2.01 (ddd, J = 12.97, 2′-fluoro[biphenyl]-4- 9.06, 4.22 Hz, 1 H)2.16-2.27 (m, 1 H) 3.14-3.20 (m, 12 H) carboxamide 3.21-3.24 (m, 1 H)4.08 (qd, J = 5.27, 1.73 Hz, 4 H) 4.13 (s, 2 H) 4.15 (br t, J = 4.95 Hz,1 H) 4.24- 4.32 (m, 2 H) 7.37 (t, J = 7.72 Hz, 1 H) 7.52-7.61 (m, 3 H)7.69 (s, 1 H) 8.86 (br d, J = 6.09 Hz, 1 H) 20-113-chloro-N-((1R,2R,4S)- 409.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.07 (s, 1H) 1.24 (s, 1 7-cyano-7- H) 1.38 (dd, J = 12.62, 4.36 Hz, 1 H)azabicyclo[2.2.1]heptan- 1.54-1.65 (m, 1 H) 1.68-1.77 (m, 1 H) 1.82 (td,J = 7.88, 3.95 2-yl)-5′-(cyanomethyl)- Hz, 1 H) 2.01 (tt, J = 8.65, 4.56Hz, 1 2′-fluoro[biphenyl]-4- H) 2.16-2.27 (m, 1 H) 2.38 (br s, 1 H) 2.52(br s, 1 H) 3.14- carboxamide 3.21 (m, 7 H) 4.0-4.12 (m, 4 H) 4.15 (t, J= 4.95 Hz, 1 H) 4.24-4.32 (m, 2 H) 7.39 (t, J = 9.49 Hz, 1 H) 7.44-7.52(m, 1 H) 7.53-7.63 (m, 3 H) 7.70 (s, 1 H) 8.85 (br d, J = 6.09 Hz, 1 H)20-12 2-chloro-N-(1R,2R,4S)- 420.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.07(s, 1 H) 1.24 (s, 1 7-cyano-7- H) 1.34-1.42 (m, 1 H) 1.55-1.66 (m,azabicyclo[2.2.1]heptan- 1 H) 1.68-1.77 (m, 1 H) 1.77-1.87 (m, 1 H) 2.01(ddd, 2-yl)-4-(6-(2-cyano-2- J = 12.90, 8.99, 4.18 Hz, 1 H) 2.18-2.23(m, propanyl)-2- 1 H) 2.37-2.49 (m, 4 H) 3.14-3.24 (m, 1 H) 4.02-4.10(m, 2 pyridinyl)benzamide H) 4.15 (t, J = 5.04 Hz, 1 H) 4.24-4.31 (m, 2H) 7.23 (s, 1 H) 7.50 (s, 1 H) 7.52-7.56 (m, 2 H) 7.70 (dd, J = 7.95,1.77 Hz, 1 H) 7.80 (d, J = 1.73 Hz, 1 H) 8.81 (br d, J = 5.90 Hz, 1 H)20-13 3-chloro-N-((1R,2R,4S)- 405.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.07(s, 4 H) 1.24 (s, 1 7-cyano-7- H) 1.40 (dd. J = 12.67, 4.31 Hz, 1 H)azabicyclo[2.2.1]heptan- 1.55-1.65 (m, 1 H) 1.68-1.77 (m, 1 H) 1.78-1.86(m, 1 H) 2-yl)-5′-(cyanomethyl)- 2.02 (ddd, J = 12.92, 8.97, 4.18 Hz, 1H) 2′-methyl[biphenyl]-4- 2.21-2.27 (m, 3 H) 2.37-2.47 (m, 1 H) 3.17 (d,J = 5.27 Hz, 2 carboxamide H) 3.90 (s, 1 H) 4.01-4.08 (m, 2 H) 4.16 (t,J = 5.04 Hz, 1 H) 4.24-4.32 (m, 1 H) 7.18 (d, J = 1.82 Hz, 1 H)7.28-7.33 (m, 1 H) 7.33-7.37 (m, 1 H) 7.39 (dd, J = 7.81, 1.63 Hz, 1 H)7.47-7.54 (m, 1 H) 8.83 (d, J = 5.99 Hz, 1 H) 20-143-chloro-N-((1R,2R,4S)- 405.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.07 (s, 1H) 1.24 (s, 1 7-cyano-7- H) 1.34-1.42 (m, 1 H) 1.55-1.66 (m,azabicyclo[2.2.1]heptan- 1 H) 1.68-1.77 (m, 1 H) 1.77-1.87 (m, 1 H) 2.01(ddd, 2-yl)-3′-(cyanomethyl)- J = 12.90, 8.99, 4.18 Hz, 1 H) 2.18-2.23(m, 4′-methyl[biphenyl]-4- 1 H) 2.37-2.49 (m, 4 H) 3.14-3.24 (m, 1 H)4.02-4.10 (m, 2 carboxamide H) 4.15 (t, J = 5.04 Hz, 1 H) 4.24-4.31 (m,2 H) 7.23 (s, 1 H) 7.50 (s, 1 H) 7.52-7.56 (m, 2 H) 7.70 (dd, J = 7.95,1.77 Hz, 1 H) 7.80 (d, J = 1.73 Hz, 1 H) 8.81 (br d, J = 5.90 Hz, 1 H)20-15 3-chloro-N-((1R,2R,4S)- 405.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.07(s, 4 H) 1.24 (s, 1 7-cyano-7- H) 1.40 (dd, J = 12.67, 4.31 Hz, 1 H)azabicyclo[2.2.1]heptan- 1.55-1.65 (m, 1 H) 1.68-1.77 (m, 1 H) 1.78-1.86(m, 1 H) 2-yl)-3′-(cyanomethyl)- 2.02 (ddd, J = 12.92, 8.97, 4.18 Hz, 1H) 5′-methyl[biphenyl]-4- 2.21-2.27 (m, 3 H) 2.37-2.47 (m, 1 H) 3.17 (d,J = 5.27 Hz, 2 carboxamide H) 3.90 (s, 1 H) 4.01-4.08 (m, 2 H) 4.16 (t,J = 5.04 Hz, 1 H) 4.24-4.32 (m, 1 H) 7.18 (d, J = 1.82 Hz, 1 H)7.28-7.33 (m, 1 H) 7.33-7.37 (m, 1 H) 7.39 (dd, J = 7.81, 1.63 Hz, 1 H)7.47-7.54 (m, 1H) 8.83 (d, J = 5.99 Hz, 1 H) 20-163-chloro-N-((1R,2R,4S)- 391.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.24 (s, 1H) 1.39 (dd, 7-cyano-7- J = 12.72, 4.27 Hz, 1 H) 1.60 (ddd,azabicyclo[2.2.1]heptan- J = 12.26, 8.72, 4.00 Hz, 1 H) 1.77-1.86 (m, 1H) 2.01 (ddd, 2-yl)-3′- J = 12.90, 9.04, 4.31 Hz, 1 H) 2.23 (br s, 1(cyanomethyl)[biphenyl]-4- H) 2.52 (br d, J = 1.82 Hz, 1 H) 4.10 (s, 2H) 4.15 (t, J = 4.90 Hz, 1 carboxamide H) 4.24-4.31 (m, 2 H) 7.47 (m, J= 8.45 Hz, 2 H) 7.53 (d, J = 7.90 Hz, 1 H) 7.72 (dd, J = 7.99, 1.73 Hz,1 H) 7.75-7.78 (m, 2 H) 7.82 (d, J = 1.73 Hz, 1 H) 8.80 (br d, J = 6.09Hz, 1 H) 20-17 3-chloro-N-((1R,2R,4S)- 431.0 1H NMR (600 MHz, DMSO-d6) δppm 1.07 (s, 2 H) 1.24 (br s, 7-cyano-7- 1 H) 1.39 (dd, J = 12.62, 4.27Hz, 1 H) azabicyclo[2.2.1]heptan- 1.60 (ddd, J = 12.38, 8.83, 3.77 Hz, 1H) 1.73 (br d, J = 12.17 Hz, 1 2-yl)-3′-(1- H) 1.78-1.87 (m, 1 H)1.98-2.07 cyanocyclobutyl)[biphenyl]- (m, 2 H) 2.23 (br s, 1 H) 2.31(dt, J = 11.24, 8.78 Hz, 1 H) 2.37- 4-carboxamide 2.47 (m, 1 H) 2.52 (brs, 1 H) 2.70- 2.81 (m, 4 H) 4.15 (t, J = 4.86 Hz, 1 H) 4.23-4.32 (m, 2H) 7.50- 7.54 (m, 2 H) 7.55 (dd, J = 8.99, 7.90 Hz, 2 H) 7.57-7.61 (m, 1H) 7.70 (d, J = 8.07 Hz, 1 H) 7.75 (s, 1 H) 7.76 (d, J = 6.98 Hz, 1 H)7.89 (d, J = 1.73 Hz, 2 H) 8.81 (br d, J = 5.99 Hz, 1 H) 20-182-chloro-N-((1R,2R,4S)- 397.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.24 (s, 1H) 1.40 (dd, 7-cyano-7- J = 12.67, 4.22 Hz, 1 H) 1.57-1.68 (m,azabicyclo[2.2.1]heptan- 1 H) 1.68-1.77 (m, 1 H) 1.78-1.85 (m, 1 H) 2.02(t, J = 8.66, 2-yl)-4-(6- 4.55 Hz, 1 H) 2.16-2.26 (m, 1 H) 2.52(methoxymethyl)-2- (br d, J = 1.82 Hz, 1 H) 4.11-4.21 (m, 1 H) 4.21-4.31(m, 2 H) pyridinyl)benzamide 4.59 (s, 2 H) 7.44 (d, J = 7.54 Hz, 1 H)7.57 (d, J = 7.99 Hz, 1 H) 7.92-8.00 (m, 2 H) 8.12 (dd, J = 7.99, 1.73Hz, 1 H) 8.21 (d, J = 1.64 Hz, 1 H) 8.84 (br d, J = 6.27 Hz, 1 H) 20-193-chloro-N-((1R,2R,4S)- 391.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.24 (s, 1H) 1.39 (dd, 7-cyano-7- J = 12.72, 4.27 Hz, 1 H) 1.60 (ddd,azabicyclo[2.2.1]heptan- J = 12.26, 8.72, 4.00 Hz, 1 H) 1.77-1.86 (m, 1H) 2.01 (ddd, 2-yl)-4′- J = 12.90, 9.04, 4.31 Hz, 1 H) 2.23 (br s, 1(cyanomethyl)[biphenyl]- H) 2.52 (br d, J = 1.82 Hz, 1 H) 4.10 (s, 2 H)4.15 (t, J = 4.90 Hz, 1 4-carboxamide H) 4.24-4.31 (m, 2 H) 7.47 (m, J =8.45 Hz, 2 H) 7.53 (d, J = 7.90 Hz, 1 H) 7.72 (dd, J = 7.99, 1.73 Hz, 1H) 7.75-7.78 (m, 2 H) 7.82 (d, J = 1.73 Hz, 1 H) 8.80 (br d, J = 6.09Hz, 1 H) 20-20 2-chloro-N-((1R,2R,4S)- 418.0 7-cyano-7-azabicyclo[2.2.1]heptan- 2-yl)-4-(5-(1- cyanocyclopropyl)-3-pyridinyl)benzamide 20-21 4-(6- 424.0 (acetyl(methyl)amino)-2-pyridinyl)-2-chloro-N- ((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan-2-yl)benzamide 20-22 2-chloro-N-((1R,2R,4S)- 392.0 1H NMR (500 MHz,DMSO-d6) δ ppm 0.80-0.90 (m, 1 H) 7-cyano-7- 1.24 (br s, 3 H) 1.39 (dd,J = 12.72, 4.02 azabicyclo[2.2.1]heptan- Hz, 5 H) 1.54-1.66 (m, 5 H)1.68-1.77 (m, 5 H) 1.78-1.91 2-yl)-4-(5- (m, 5 H) 2.02 (ddd, J = 12.78,9.02, 4.02 (cyanomethyl)-3- Hz, 5 H) 2.19-2.28 (m, 5 H) 3.31 (s, 9 H)4.14-4.18 (m, 15 H) pyridinyl)benzamide 4.24-4.32 (m, 10 H) 7.59 (d, J =7.91 Hz, 5 H) 7.80 (dd, J = 7.91, 1.82 Hz, 5 H) 7.94 (d, J = 1.69 Hz, 5H) 8.17 (t, J = 2.14 Hz, 5 H) 8.62 (d, J = 2.08 Hz, 5 H) 8.85 (d, J =5.84 Hz, 5 H) 8.93 (d, J = 2.21 Hz, 5 H) 20-23 2-chloro-N-((1R,2R,4S)-392.0 1H NMR (500 MHz, DMSO-d6) δ ppm 0.86 (br t, J = 6.88 Hz,7-cyano-7- 1 H) 1.17 (br t, J = 7.07 Hz, 1 H) 1.22-1.31azabicyclo[2.2.1]heptan- (m, 2 H) 1.33-1.46 (m, 5 H) 1.54-1.66 (m, 5 H)1.68-1.77 2-yl)-4-(4- (m, 5 H) 1.77-1.88 (m, 5 H) 1.95- (cyanomethyl)-2-2.08 (m, 5 H) 2.17-2.30 (m, 5 H) 3.31 (s, 11 H) 4.14-4.23 (m,pyridinyl)benzamide 13 H) 4.24-4.33 (m, 10 H) 7.44 (d, J = 4.54 Hz, 4 H)7.54-7.64 (m, 5 H) 7.78 (dd, J = 7.98, 1.49 Hz, 1 H) 7.93 (d, J = 1.56Hz, 1 H) 8.04-8.15 (m, 8 H) 8.21 (d, J = 1.30 Hz, 4 H) 8.72 (d, J = 5.06Hz, 4 H) 8.79-8.94 (m, 5 H) 20-24 N-((1R,2R,4S)-7-cyano- 398.0 1H NMR(500 MHz, DMSO-d6) δ ppm 0.83-0.88 (m, 1 H) 7- 1.07 (s, 1 H) 1.17 (td, J= 6.81, 1.43 Hz, 1 H) 1.22-1.31 (m, 2 H) azabicyclo[2.2.1]heptan- 1.41(dd, J = 12.65, 4.48 Hz, 1 H) 1.58-1.67 (m, 1 H) 1.68-1.772-yl)-4-(6-(1- (m, 1 H) 1.78-1.87 (m, 5 H) 1.89-1.99 (m, 1 H) 2.17-2.28cyanocyclopropyl)-2- (m, 1 H) 2.41 (s, 3 H) 3.08 (br s, 1 H) 4.15 (t, J= 4.93 Hz, 1 H) pyridinyl)-2- 4.23-4.33 (m, 2 H) 7.45 (d, J = 7.67 Hz, 1H) 7.50-7.56 (m, 1 methylbenzamide H) 7.86-7.96 (m, 4 H) 8.62 (d, J =6.10 Hz, 1 H) 20-25 3-chloro-N-((1R,2R,4S)- 416.4 1H NMR (600 MHz,DMSO-d6) δ ppm 1.06-1.08 (m, 5 H) 7-cyano-7- 1.35-1.42 (m, 1 H)1.58-1.64 (m, 1 H) azabicyclo[2.2.1]heptan- 1.64-1.68 (m, 1 H) 1.69-1.75(m, 1 H) 1.77-1.79 (m, 1 H) 2-yl)-3′-(1- 1.82 (br dd, J = 7.54, 4.36 Hz,1 H) 2.01 cyanocyclopropyl)]biphenyl]- (ddd, J = 12.97, 9.01, 4.27 Hz, 1H) 2.18-2.28 (m, 1 H) 2.51- 4-carboxamide 2.60 (m, 1 H) 3.90 (s, 1 H)4.15 (t, J = 5.00 Hz, 1 H) 4.24-4.32 (m, 1 H) 7.45 (d, J = 7.88 Hz, 1 H)7.50-7.57 (m, 2 H) 7.66 (dt, J = 8.04, 1.25 Hz, 1 H) 7.73 (dd, J = 7.99,1.73 Hz, 1 H) 7.87 (d, J = 1.73 Hz, 1 H) 8.81 (br d, J = 5.90 Hz, 1 H)20-26 2-chloro-N-((1R,2R,4S)- 392.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.40(dd, J = 12.72, 4.27 7-cyano-7- Hz, 1 H) 1.57-1.65 (m, 1 H) 1.68-azabicyclo[2.2.1]heptan- 1.77 (m, 1 H) 1.77-1.87 (m, 1 H) 2.02 (ddd, J =12.97, 9.06, 4.31 2-yl)-4-(2- Hz, 1 H) 2.19-2.27 (m, 1 H) 2.51-(cyanomethyl)-3- 2.60 (m, 1 H) 3.17 (d, J = 5.27 Hz, 1 H) 3.23-3.28 (m,1 H) pyridinyl)benzamide 4.12-4.19 (m, 3 H) 4.24-4.32 (m, 2 H) 7.47 (dd,J = 7.81, 1.73 Hz, 1 H) 7.51 (dd, J = 7.72, 4.81 Hz, 1 H) 7.57 (d, J =8.55 Hz, 1 H) 7.63 (d, J = 1.63 Hz, 1 H) 7.74 (dd, J = 7.77, 1.68 Hz, 1H) 8.65 (dd, J = 4.81, 1.73 Hz, 1 H) 8.86 (d, J = 5.90 Hz, 1 H) 20-27N-((1R,2R,4S)-7-cyano- 452.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.06-1.09(m, 2 H) 7- 1.24 (s, 1 H) 1.32-1.40 (m, 1 H) 1.55-azabicyclo[2.2.1]heptan- 1.62 (m, 1 H) 1.67-1.77 (m, 1 H) 1.79-1.89 (m,5 H) 1.94 2-yl)-4-(6-(1- (ddd, J = 12.94, 9.04, 4.36 Hz, 1 H) 2.18-cyanocyclopropyl)-2- 2.28 (m, 1 H) 3.23-3.28 (m, 1 H) 4.15 (t, J = 5.00Hz, 1 H) 4.23 pyridinyl)-2- (t, J = 4.63 Hz, 1 H) 4.26-4.32 (m, 1 H)7.58 (trifluoromethyl)benzamide (dd, J = 7.81, 0.73 Hz, 1 H) 7.69 (d, J= 7.90 Hz, 1 H) 8.00 (t, J = 7.81 Hz, 1 H) 8.07 (dd, J = 7.90, 0.64 Hz,1 H) 8.42 (d, J = 7.77 Hz, 1 H) 8.43 (s, 1 H) 8.89 (d, J = 6.36 Hz, 1 H)20-28 N-((1R,2R,4S)-7-cyano- 402.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.24(s, 1H) 1.44 (dd, 7- J = 12.76, 4.50 Hz, 1 H) 1.60-1.67 (m,azabicyclo[2.2.1]heptan- 1 H) 1.68-1.76 (m, 1 H) 1.79-1.89 (m, 5 H) 1.94(ddd, 2-yl)-4-(6-(1- J = 12.85, 8.99, 4.22 Hz, 1 H) 2.18-2.29 (m,cyanocyclopropyl)-2- 1 H) 3.22-3.28 (m, 1 H) 4.16 (t, J = 4.86 Hz, 1 H)4.24-4.28 (m, pyridinyl)-2- 1 H) 4.30 (br dd, J = 11.22, 4.95 Hz,fluorobenzamide 1 H) 7.58 (d, J = 7.36 Hz, 1 H) 7.68 (t, J = 7.72 Hz, 1H) 7.95- 8.02 (m, 4 H) 8.72 (br d, J = 6.27 Hz, 1 H) 20-29N-((1R,2R,4S)-7-cyano- 390.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.07 (s, 2H) 1.37 (dd, 7- J = 12.72, 4.63 Hz, 1 H) 1.55-1.65 (m,azabicyclo[2.2.1]heptan- 1 H) 1.71 (br d, J = 12.62 Hz, 1 H) 1.76-1.84(m, 1 H) 1.93 (ddd, 2-yl)-4-(1-methyl-1H- J = 13.03, 8.99, 4.13 Hz, 1 H)2.20- pyrazol-3-yl)-2- 2.26 (m, 1 H) 3.22-3.28 (m, 1 H) 3.89-3.94 (m, 3H) 4.15 (t, (trifluoromethyl)benzamide J = 4.90 Hz, 1 H) 4.22 (t, J =4.68 Hz, 1 H) 4.27 (br dd, J = 11.26, 4.72 Hz, 1 H) 6.90 (d, J = 2.27Hz, 1 H) 7.58 (d, J = 7.99 Hz, 1 H) 7.80 (d, J = 2.27 Hz, 1 H) 8.12 (d,J = 8.07 Hz, 1 H) 8.84 (d, J = 6.36 Hz, 1H) 20-30 N-((1R,2R,4S)-7-cyano-426.0 1H NMR (600 MHz, DMSO-d6) δ ppm 0.99-1.10 (m, 1 H) 7- 1.37 (dd, J= 12.72, 4.63 Hz, 1 H) 1.55- azabicyclo[2.2.1]heptan- 1.65 (m, 1 H)1.68-1.77 (m, 1 H) 1.77-1.86 (m, 1 H) 1.95 2-yl)-4-(imidazo[1,5- (ddd, J= 13.06, 9.11, 4.18 Hz, 1 H) 2.21- a]pyridin-6-yl)-2- 2.28 (m, 1 H)2.51-2.56 (m, 1 H) 3.17 (d, J = 5.09 Hz, 1 H) 4.16(trifluoromethyl)benzamide (t, J = 4.90 Hz, 1 H) 4.23 (t, J = 4.68 Hz, 1H) 4.29 (br dd, J = 11.31, 4.68 Hz, 1 H) 7.22 (dd, J = 9.45, 1.54 Hz, 1H) 7.42 (s, 1 H) 7.67 (br d, J = 7.90 Hz, 1 H) 7.69 (br d, J = 9.45 Hz,1 H) 8.06 (dd, J = 7.95, 1.59 Hz, 1H) 8.08 (s, 1 H) 8.42 (s, 1 H) 8.88(br d, J = 6.36 Hz, 1 H) 8.90 (d, J = 1.36 Hz, 1 H) 20-31N-((1R,2R,4S)-7-cyano- 340.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.45 (dd, J= 12.72, 4.54 7- Hz, 1 H) 1.62-1.74 (m, 2 H) 1.76-1.85 (m, 1H)azabicyclo[2.2.1]heptan- 1.93 (ddd, J = 12.85, 8.90, 4.31 Hz, 1 H)2.17-2.25 2-yl)-2-fluoro-4-(1- (m, 1 H) 3.23-3.28 (m, 1 H) 3.90methyl-1H-pyrazol-3- (s, 3 H) 4.15 (t, J = 4.90 Hz, 1 H) 4.22-4.26 (m, 1H) 4.26-4.32 yl)benzamide (m, 1 H) 6.83 (d, J = 2.36 Hz, 1 H) 7.59 (t, J= 7.77 Hz, 1 H) 7.65 (dd, J = 11.72, 1.45 Hz, 1 H) 7.70 (dd, J = 7.99,1.45 Hz, 1 H) 7.78 (d, J = 2.18 Hz, 1 H) 8.62 (br d, J = 6.18 Hz, 1 H)20-32 N-((1R,2R,4S)-7-cyano- 376.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.45(dd, J = 12.81, 4.54 7- Hz, 1 H) 1.62-1.75 (m, 2 H) 1.78-azabicyclo[2.2.1]heptan- 1.88 (m, 1 H) 1.94 (ddd, J = 12.92, 8.97, 4.27Hz, 1 H) 2.18-2.27 2-yl)-2-fluoro-4- (m, 1 H) 3.23-3.28 (m, 1 H) 3.32-(imidazo[1,5-a]pyridin- 3.43 (m, 1 H) 4.16 (t, J = 5.00 Hz, 1 H)4.24-4.28 (m, 1 H) 4.28- 6-yl)benzamide 4.33 (m, 1 H) 7.20 (dd, J =9.54, 1.54 Hz, 1 H) 7.41 (s, 1 H) 7.63-7.71 (m, 4 H) 8.41 (s, 1 H) 8.69(br d, J = 6.18 Hz, 1 H) 8.86 (d, J = 1.27 Hz, 1 H) 20-332,6-dichloro-N- 391.8 1H NMR (600 MHz, DMSO-d6) δ ppm 1.05-1.09 (m, 2 H)((1R,2R,4S)-7-cyano-7- 1.09-1.17 (m, 1 H) 1.24 (br, 1 H) 1.33azabicyclo[2.2.1]heptan- (dd, J = 12.76, 4.13 Hz, 1 H) 1.48-1.60 (m, 1H) 1.66-1.77 (m, 2-yl)-4-(1-methyl-1H- 1 H) 1.77-1.85 (m, 1 H) 2.06(ddd, pyrazol-3-yl)benzamide J = 12.99, 9.08, 4.18 Hz, 1 H) 2.25 (br s,1 H) 2.38 (br s, 1 H) 3.18-3.29 (m, 2 H) 3.32-3.41 (m, 1 H) 3.90 (s, 3H) 4.16 (t, J = 4.90 Hz, 1 H) 4.23-4.30 (m, 2 H) 6.91 (d, J = 2.27 Hz, 1H) 7.79 (d, J = 2.27 Hz, 1 H) 7.89 (s, 2 H) 9.03 (br d, J = 6.00 Hz, 1H) 20-34 2,6-dichloro-N- 427.8 1H NMR (600 MHz, DMSO-d6) δ ppm 1.33 (dd,J = 12.67, 4.04 ((1R,2R,4S)-7-cyano-7- Hz, 1 H) 1.53-1.61 (m, 1 H) 1.68-azabicyclo[2.2.1]heptan- 1.78 (m, 1H) 1.78-1.87 (m, 1 H) 2.07 (ddd, J =12.94, 9.04, 4.27 2-yl)-4-(imidazo[1,5- Hz, 1 H) 2.26 (br t, J = 10.85Hz, 1 a]pyridin-6- H) 3.17 (br d, J = 5.18 Hz, 1 H) 3.22-3.29 (m, 2 H)3.32-3.40 yl)benzamide (m, 1 H) 4.16 (t, J = 4.95 Hz, 1 H) 4.24-4.32 (m,2 H) 7.21 (dd, J = 9.54, 1.54 Hz, 1 H) 7.41 (s, 1 H) 7.67 (d, J = 9.54Hz, 1 H) 7.90 (s, 2 H) 8.39 (s, 1 H) 8.91 (s, 1 H) 9.06 (br d, J = 6.09Hz, 1 H) 20-35 2-chloro-N-((1R,2R,4S)- 378.8 1H NMR (600 MHz, DMSO-d6) δppm 0.78-0.89 (m, 1 H) 7-cyano-7- 1.24 (s, 2 H) 1.28 (s, 1 H) 1.33-1.42(m, azabicyclo[2.2.1]heptan- 1 H) 1.55-1.65 (m, 1 H) 1.74 (br d, J =10.54 Hz, 1 H) 2-yl)-4-(5-cyano-2- 1.78-1.87 (m, 1 H) 2.02 (ddd, J =12.92, 9.01, pyrimidinyl)benzamide 4.22 Hz, 1 H) 2.17-2.28 (m, 1 H) 2.52(br d, J = 1.82 Hz, 1 H) 3.23-3.28 (m, 1 H) 4.16 (t, J = 4.95 Hz, 1 H)4.25-4.33 (m, 2 H) 7.68 (d, J = 7.90 Hz, 1 H) 7.73 (br s, 1 H) 8.43 (dd,J = 7.95, 1.59 Hz, 1 H) 8.46 (d, J = 1.64 Hz, 1 H) 8.63 (s, 1 H) 8.94(br d, J = 6.08 Hz, 1 H) 9.43 (s, 2 H) 20-36 2-chloro-N-((1R,2R,4S)-378.8 1H NMR (600 MHz, DMSO-d6) δ ppm 1.24 (s, 1 H) 1.39 (dd, 7-cyano-7-J = 12.67, 4.31 Hz, 1 H) 1.55-1.65 (m, azabicyclo[2.2.1]heptan- 1 H)1.69-1.78 (m, 1 H) 1.78-1.87 (m, 1 H) 2.02 (ddd, 2-yl)-4-(4-cyano-2- J =12.94, 8.99, 4.31 Hz, 1 H) 2.24 (br t, pyrimidinyl)benzamide J = 11.04Hz, 1 H) 2.51-2.60 (m, 1 H) 3.17-3.28 (m, 2 H) 4.16 (t, J = 4.95 Hz, 1H) 4.25-4.33 (m, 2 H) 7.67 (d, J = 7.99 Hz, 1 H) 8.15 (d, J = 4.90 Hz, 1H) 8.38 (dd, J = 7.99, 1.64 Hz, 1 H) 8.40 (d, J = 1.63 Hz, 1 H) 8.93 (brd, J = 5.99 Hz, 1 H) 9.28 (d, J = 4.90 Hz, 1 H) 20-372-chloro-N-((1R,2R,4S)- 368.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.24 (brs, 1 H) 1.39 7-cyano-7- (dd, J = 12.72, 4.27 Hz, 1 H) 1.55-1.64azabicyclo[2.2.1]heptan- (m, 1 H) 1.74 (br d, J = 12.44 Hz, 1 H)1.78-1.86 (m, 1 H) 2.02 2-yl)-4-(6--methyl-2- (ddd, J = 12.94, 9.08,4.22 Hz, 1 H) pyrazinyl)benzamide 2.20-2.27 (m, 1 H) 2.38 (br s, 1 H)2.57-2.62 (m, 3 H) 3.23- 3.29 (m, 2 H) 3.32-3.43 (m, 1 H) 4.16 (t, J =4.86 Hz, 1 H) 4.24-4.32 (m, 2 H) 7.60 (d, J = 7.90 Hz, 1 H) 8.17 (dd, J= 7.99, 1.73 Hz, 1 H) 8.26 (d, J = 1.73 Hz, 1 H) 8.58 (s, 1 H) 8.87 (brd, J = 5.99 Hz, 1 H) 9.15 (s, 1 H) 20-38 2-chloro-N-((1R,2R,4S)- 368.01H NMR (600 MHz, DMSO-d6) δ ppm 1.24 (s, 1H) 1.34-1.42 7-cyano-7- (m, 1H) 1.55-1.65 (m, 1 H) 1.68-1.77 (m, 1 H) azabicyclo[2.2.1]heptan-1.77-1.86 (m, 1 H) 2.02 (ddd, J = 12.97, 9.06, 4.13 2-yl)-4-(5-methyl-2-Hz, 1 H) 2.17-2.27 (m, 1 H) 2.56 pyrazinyl)benzamide (s, 3 H) 4.16 (t, J= 4.90 Hz, 1 H) 4.25-4.32 (m, 2 H) 7.59 (d, J = 7.99 Hz, 1 H) 8.15 (dd,J = 7.99, 1.63 Hz, 1 H) 8.24 (d, J = 1.63 Hz, 1 H) 8.65 (d, J = 0.91 Hz,1 H) 8.85 (br d, J = 6.08 Hz, 1 H) 9.21 (d, J = 1.45 Hz, 1 H) 20-392-chloro-N-((1R,2R,4S)- 378.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.07 (d, J= 1.00 Hz, 1 H) 7-cyano-7- 1.39 (dd, J = 12.90, 4.09 Hz, 1 H) 1.56-1.65(m, 1 H) azabicyclo[2.2.1]heptan- 1.68-1.77 (m, 1 H) 1.78-1.86 (m, 1 H)2.02 2-yl)-4-(4-cyano-2- (ddd, J = 12.97, 9.15, 4.13 Hz, 1 H) 2.18-2.27(m, 1 H) pyridinyl)benzamide 3.23-3.28 (m, 1 H) 4.16 (t, J = 5.00 Hz, 1H) 4.24-4.32 (m, 2 H) 7.61 (s, 1 H) 7.89 (dt, J = 4.97, 1.19 Hz, 1 H)8.20 (d, J = 8.15 Hz, 1 H) 8.30 (s, 1 H) 8.63 (d, J = 1.00 Hz, 1 H) 8.87(br d, J = 5.81 Hz, 1 H) 8.94 (d, J = 5.73 Hz, 1 H) 20-402-chloro-N-((1R,2R,4S)- 367.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.06-1.09(m, 6 H) 7-cyano-7- 1.24 (s, 1 H) 1.40 (dd, J = 12.85, 4.13 Hz,azabicyclo[2.2.1]heptan- 1 H) 1.55-1.67 (m, 1 H) 1.78-1.86 (m, 1 H) 2.02(ddd, 2-yl)-4-(6-methyl-2- J = 12.97, 9.06, 4.04 Hz, 1 H) 2.56 (s, 2 H)pyridinyl)benzamide 3.90 (s, 1 H) 4.16 (t, J = 4.90 Hz, 1 H) 4.22-4.31(m, 2 H) 7.26- 7.32 (m, 1 H) 7.55 (d, J = 7.99 Hz, 1 H) 7.81 (t, J =7.72 Hz, 1 H) 7.87 (d, J = 7.72 Hz, 1 H) 8.11 (dd, J = 7.99, 1.73 Hz, 1H) 8.21 (d, J = 1.64 Hz, 1 H) 8.83 (br d, J = 5.90 Hz, 1 H) 20-412-chloro-N-((1R,2R,4S)- 368.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.39 (dd,J = 12.72, 4.18 7-cyano-7- Hz, 1H) 1.55-1.64 (m, 1 H) 1.69-azabicyclo[2.2.1]heptan- 1.78 (m, 1 H) 1.78-1.86 (m, 1 H) 2.01 (ddd, J =12.81, 8.95, 4.22 2-yl)-4-(2-methyl-4- Hz, 1 H) 2.24 (br t, J = 11.04Hz, 1 pyrimidinyl)benzamide H) 2.39-2.48 (m, 1 H) 2.71 (s, 3 H) 3.27 (s,1 H) 4.16 (t, J = 4.95 Hz, 1 H) 4.25-4.32 (m, 2 H) 7.62 (d, J = 7.99 Hz,1 H) 8.00 (d, J = 5.36 Hz, 1 H) 8.22 (dd, J = 7.99, 1.27 Hz, 1 H) 8.32(d, J = 1.54 Hz, 1 H) 8.81 (d, J = 5.36 Hz, 1 H) 8.89 (br d, J = 5.90Hz, 1 H) 20-42 2-chloro-N-((1R,2R,4S)- 368.0 1H NMR (600 MHz, DMSO-d6) δppm 1.24 (s, 1 H) 1.39 (dd, 7-cyano-7- J = 12.76, 4.22 Hz, 1 H)1.55-1.64 (m, azabicyclo[2.2.1]heptan- 1 H) 1.69-1.78 (m, 1 H) 1.79-1.86(m, 1 H) 2.03 (ddd, 2-yl)-4-(6-methyl-3- J = 12.94, 9.04, 4.18 Hz, 1 H)2.24 (br s, 1 H) pyridazinyl)benzamide 2.38 (br d, J = 1.91 Hz, 1 H)2.52-2.57 (m, 1 H) 2.68 (s, 3 H) 3.22-3.28 (m, 1 H) 4.16 (t, J = 4.86Hz, 1 H) 4.26-4.32 (m, 2 H) 7.62 (d, J = 7.99 Hz, 1 H) 7.71 (d, J = 8.81Hz, 1 H) 8.17 (dd, J = 7.99, 1.64 Hz, 1 H) 8.24 (d, J = 8.72 Hz, 1 H)8.27 (d, J = 1.63 Hz, 1 H) 8.87 (br d, J = 6.18 Hz, 1 H) 20-432-chloro-N-((1R,2R,4S)- 403.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.04-1.11(m, 1 H) 7-cyano-7- 1.39 (dd, J = 12.72, 4.27 Hz, 1 H) 1.57-1.64 (m, 1H) azabicyclo[2.2.1]heptan- 1.69-1.77 (m, 1 H) 1.78-1.86 (m, 1 H) 2.022-yl)-4-(6- (ddd, J = 12.83, 8.97, 4.27 Hz, 1 H) 2.18-(difluoromethlyl)-2- 2.28 (m, 1 H) 3.21-3.28 (m, 1 H) 4.16 (t, J = 5.00Hz, 1 H) pyridinyl)benzamide 4.24-4.32 (m, 2 H) 6.96 (se 1 H) 7.01- 7.14(m, 1 H) 7.61 (d, J = 7.99 Hz, 1 H) 7.73 (d, J = 7.63 Hz, 1 H) 8.11-8.20(m, 2H) 8.27 (d, J = 9.24 Hz, 1 H) 8.26 (s, 1 H) 8.87 (br d, J = 6.00Hz, 1 H) 20- 2-chloro-N-((1R,2R,4S)- 392.0 1H NMR (600 MHz, DMSO-d6) δppm 1.07 (s, 1 H) 1.39 (dd, 44 7-cyano-7- J = 12.76, 4.31 Hz, 1 H)1.56-1.67 (m, azabicyclo[2.2.1]heptan- 1 H) 1.68-1.78 (m, 1 H) 1.82 (td,J = 7.86, 3.72 Hz, 1 H) 2.02 2-yl)-4-(6- (ddd, J = 13.06, 9.06, 4.22 Hz,1 H) 2.16-2.27 (cyanomethyl)-2- (m, 1 H) 2.37-2.47 (m, 1 H) 2.51-2.56(m, 1 H) 3.16-3.28 (m, 1 H) pyridinyl)benzamide 4.16 (t, J = 5.04 Hz, 1H) 4.25-4.33 (m, 4 H) 7.46 (d, J = 7.63 Hz, 1 H) 7.60 (d, J = 7.99 Hz, 1H) 7.97 (t, J = 7.81 Hz, 1 H) 8.06 (d, J = 7.90 Hz, 1 H) 8.15 (dd, J =7.99, 1.73 Hz, 1 H) 8.26 (d, J = 1.64 Hz, 1 H) 8.85 (br d, J = 6.08 Hz,1 H) 20-45 2-chloro-N-((1R,2R,4S)- 418.8 1H NMR (600 MHz, DMSO-d6) δ ppm1.07 (s, 1 H) 1.13 (br d, 7-cyano-7- J = 7.27 Hz, 1 H) 1.24 (s, 1 H)1.39 azabicyclo[2.2.1]heptan- (dd, J = 12.67, 4.31 Hz, 1 H) 1.57-1.64(m, 1 H) 1.74 (br d, 2-yl)-4-(6- J = 12.72 Hz, 1 H) 1.78-1.87 (m, 1 H)(difluoromethoxy)-2- 2.02 (ddd, J = 12.87, 8.97, 4.13 Hz, 1 H) 2.24 (brs, 1 H) 2.37- pyridinyl)benzamide 2.47 (m, 1 H) 2.52 (br d, J = 1.91 Hz,1 H) 3.16-3.28 (m, 2 H) 4.16 (t, J = 4.90 Hz, 1 H) 4.24-4.32 (m, 2 H)7.11 (d, J = 8.08 Hz, 1 H) 7.58 (d, J = 7.99 Hz, 1H) 7.93-7.99 (m, 1 H)8.04 (t, J = 7.93 Hz, 1 H) 8.08-8.17 (m, 1 H) 8.25 (d, J = 1.64 Hz, 1 H)8.84 (br d, J = 5.72 Hz, 1H) 20-46 2-chloro-N-((1R,2R,4S)- 417.0 1H NMR(600 MHz, DMSO-d6) δ ppm 1.07 (s, 4 H) 1.24 (s, 1 7-cyano-7- H) 1.39(dd, J = 12.76, 4.31 Hz, 1 H) azabicyclo[2.2.1]heptan- 1.55-1.65 (m, 1H) 1.69-1.78 (m, 1 H) 1.78-1.89 (m, 1 H) 2-yl)-4-(6-(1,1- 2.00-2.07 (m,2 H) 2.08-2.13 (m, 2 H) difluromethyl)-2- 2.24 (br t, J = 11.26 Hz, 1 H)2.52 (br d, J = 1.82 Hz, 1 H) 3.16- pyridinyl)benzamide 3.28 (m, 1 H)3.90 (s, 1 H) 4.16 (t, J = 4.90 Hz, 1 H) 4.25-4.32 (m, 2 H) 7.60 (d, J =7.99 Hz, 1 H) 7.73 (dd, J = 7.72, 0.73 Hz, 1H) 8.12 (t, J = 7.86 Hz, 1H) 8.17 (dd, J = 7.99, 1.64 Hz, 1 H) 8.24 (d, J = 10.95 Hz, 1 H) 8.24(s, 1 H) 8.86 (br d, J = 6.09 Hz, 1 H) 20-47 2-chloro-N-((1R,2R,4S)-394.0 1H NMR (600 MHz, DMSO-d6) δ ppm 1.06-1.16 (m, 4 H) 7-cyano-7- 1.24(br s, 1 H) 1.38 (dd, J = 12.62, 4.18 azabicyclo[2.2.1]heptan- Hz, 1 H)1.55-1.66 (m, 1 H) 1.73 (br d, J = 12.99 Hz, 1 H) 1.822-yl)-4-(6-cyclopropyl- (br dd, J = 7.18, 3.00 Hz, 1 H) 2.012-pyrazinyl)benzamide (ddd, J = 12.81, 8.95, 4.31 Hz, 1 H) 2.23 (br s, 1H) 2.26-2.31 (m, 1 H) 3.27 (br s, 1 H) 4.15 (t, J = 4.90 Hz, 1 H)4.24-4.32 (m, 2 H) 7.59 (d, J = 7.90 Hz, 1 H) 8.12 (dd, J = 7.99, 1.64Hz, 1 H) 8.20 (d, J = 1.54 Hz, 1 H) 8.64 (s, 1 H) 8.84 (br d, J = 5.90Hz, 1 H) 9.06 (s, 1 H) 20-48 2-chloro-N-((1R,2R,4S)- 378.0 1H NMR (600MHz, DMSO-d6) δ ppm 1.04-1.11 (m, 1 H) 7-cyano-7- 1.39 (dd, J = 12.72,4.27 Hz, 1 H) 1.57- azabicyclo[2.2.1]heptan- 1.64 (m, 1 H) 1.69-1.77 (m,1 H) 1.78-1.86 (m, 1 H) 2.02 2-yl)-4-(6-cyano-2- (ddd, J = 12.83, 8.97,4.27 Hz, 1 H) 2.18- pyridinyl)benzamide 2.28 (m, 1 H) 3.21-3.28 (m, 1 H)4.16 (t, J = 5.00 Hz, 1 H) 4.24- 4.32 (m, 2 H) 6.96 (s, 1 H) 7.01- 7.14(m, 1 H) 7.61 (d, J = 7.99 Hz, 1 H) 7.73 (d, J = 7.63 Hz, 1 H) 8.11-8.20(m, 2 H) 8.27 (d, J = 9.24 Hz, 1 H) 8.26 (s, 1 H) 8.87 (br d, J = 6.00Hz, 1 H) 20-49 2-chloro-N-((1R,2R,4S)- 418.0 1H NMR (600 MHz, DMSO-d6) δppm 1.24 (s, 1 H) 1.44 (dd, 7-cyano-7- J = 12.76, 4.50 Hz, 1 H)1.60-1.67 (m, azabicyclo[2.2.1]heptan- 1 H) 1.68-1.76 (m, 1 H) 1.79-1.89(m, 5 H) 1.94 (ddd, 2-yl)-4-(6-(1- J = 12.85, 8.99, 4.22 Hz, 1 H)2.18-2.29 (m, cyanocyclopropyl)-2- 1 H) 3.22-3.28 (m, 1 H) 4.16 (t, J =4.86 Hz, 1 H) 4.24-4.28 (m, pyridinyl)benzamide 1 H) 4.30 (br dd, J =11.22, 4.95 Hz, 1 H) 7.58 (d, J = 7.36 Hz, 1 H) 7.68 (t, J = 7.72 Hz, 1H) 7.95- 8.02 (m, 4 H) 8.72 (br d, J = 6.27 Hz, 1 H) 20-502-chloro-N-((1R,2R,4S)- 451.0 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.90(t, J = 6.94 7-cyano-7- Hz, 4 H) 1.18 (dd, J = 12.98, 4.41 Hz,azabicyclo[2.2.1]heptan- 5 H) 1.25-1.34 (m, 9 H) 1.60-1.66 (m, 5 H)1.96-2.15 (m, 15 2-yl)-4-(6-(2,2,2- H) 2.55-2.61 (m, 5 H) 4.11-4.14trifluoroethoxy)-2- (m, 5 H) 4.49-4.52 (m, 4 H) 4.53-4.59 (m, 5 H) 4.89(q, pyridinyl)benzamide J = 8.56 Hz, 9 H) 6.53 (br d, J = 5.71 Hz, 4 H)6.92 (d, J = 8.30 Hz, 4 H) 7.27 (s, 1 H) 7.46 (d, J = 7.53 Hz, 5 H) 7.77(t, J = 7.85 Hz, 5 H) 7.86 (d, J = 8.17 Hz, 4 H) 7.96 (dd, J = 8.17,1.69 Hz, 4 H) 8.06 (d, J = 1.69 Hz, 4 H) 20-51 2-chloro-N-((1R,2R,4S)-392.0 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40 (dd, J = 12.72, 4.027-cyano-7- Hz, 4 H) 1.55-1.65 (m, 4 H) 1.68- azabicyclo[2.2.1]heptan-1.78 (m, 4 H) 1.78-1.90 (m, 4 H) 1.95-2.10 (m, 5 H) 2.18-2-yl)-4-(imidazo[1,2- 2.28 (m, 4 H) 2.83 (s, 1H) 2.96-3.12 a]pyridin-6-(m, 1H) 3.32-3.36 (m, 1 H) 4.16 (t, J = 4.87 Hz, 4 H) 4.24-4.32yl)benzamide (m, 8 H) 7.57 (d, J = 7.91 Hz, 4 H) 7.62-7.78 (m, 17 H)7.90 (d, J = 1.69 Hz, 4 H) 7.98 (s, 4 H) 8.14 (s, 2 H) 8.84 (d, J = 5.97Hz, 4 H) 9.07 (s, 4 H) 20-52 2-chloro-N-((1R,2R,4S)- 406.0 1H NMR (500MHz, DMSO-d6) δ ppm 1.17 (t, J = 7.14 Hz, 4 H) 7-cyano-7- 1.43 (dd, J =12.72, 4.28 Hz, 3 H) 1.58-1.68 (m, 3 H) azabicyclo[2.2.1]heptan-1.70-1.78 (m, 3 H) 1.78-1.88 (m, 3 H) 1.96-2.07 2-yl)-4-(1-methyl-1H-(m, 6 H) 2.19-2.30 (m, 3 H) 3.32 indazol-7-yl)benzamide (s, 2 H)3.63-3.66 (m, 8 H) 4.03 (q, J = 7.14 Hz, 2 H) 4.16 (t, J = 4.93 Hz, 3 H)4.25-4.36 (m, 6 H) 5.75 (s, 1 H) 7.17-7.27 (m, 6 H) 7.49-7.60 (m, 6 H)7.67 (d, J = 1.43 Hz, 3 H) 7.80-7.88 (m, 3 H) 8.15-8.18 (m, 3 H) 8.89(d, J = 5.97 Hz, 3 H) 20-53 2-chloro-N-((1R,2R,4S)- 406.0 1H NMR (500MHz, DMSO-d6) δ ppm 1.38-1.44 (m, 1H) 7-cyano-7- 1.58-1.65 (m, 1 H)1.69-1.77 (m, 1 H) azabicyclo[2.2.1]heptan- 1.78-1.87 (m, 1 H) 1.98-2.05(m, 1H) 2.25 (br s, 4 H) 2.29 (br 2-yl)-4-(7- s, 1 H) 2.32-2.37 (m, 1 H)3.31-3.34 methylimidazo[1,2- (m, 5 H) 4.08-4.18 (m, 2 H) 4.25-4.33 (m, 3H) 7.48 (br a]pyridin-6- d, J = 7.66 Hz, 5 H) 7.54 (br d, J = 7.79yl)benzamide Hz, 3 H) 7.62 (s, 2 H) 7.87 (br d, J = 8.17 Hz, 1 H) 8.48(br s, 1 H) 8.87 (br d, J = 5.71 Hz, 1 H) 20-54 2-chloro-N-((1R,2R,4S)-406.0 1H NMR (500 MHz, DMSO-d6) δ 1.36-1.50 (m, 2H), 1.56-1.667-cyano-7- (m, 2H), 1.69-1.78 (m, 2H), 1.78-1.93 (m, 2H), 1.96-2.15 (m,azabicyclo[2.2.1]heptan- 2H), 2.22-2.47 (m, 14H), 2.52-2.58 (m, 1H),2.99 (br s, 1H), 2-yl)-4-(2- 3.05 (s, 1H), 3.11-3.25 (m, 3H), 3.35 (brs, 8H), 4.10-4.21 (m, methylimidazo[1,2- 2H), 4.25-4.34 (m, 4H), 6.80(td, J = 6.71, 1.10 Hz, 1H), 6.92 (td, a]pyridin-6- J = 6.84, 1.10 Hz,2H), 7.08-7.21 (m, 2H), 7.29 (ddd, J = 8.99, yl)benzamide 6.78, 1.10 Hz,2H), 7.38-7.44 (m, 1H), 7.50-7.72 (m, 19H), 7.85 (s, 1H), 8.18 (br s,2H), 8.29 (d, J = 6.74 Hz, 2H), 8.43 (dt, J = 6.75, 1.10 Hz, 1H), 8.80(d, J = 10.12 Hz, 1H), 8.89 (d, J = 5.97 Hz, 2H) 20-552-chloro-N-((1R,2R,4S)- 392.0 1H NMR (500 MHz, DMSO-d6) δ ppm 1.39 (dd,J = 12.72, 4.02 7-cyano-7- Hz, 1 H) 1.56-1.65 (m, 1 H) 1.68-azabicyclo[2.2.1]heptan- 1.87 (m, 2 H) 1.95-2.09 (m, 1 H) 2.19-2.27 (m,1 H) 3.11- 2-yl)-4-(imidazol[1,2- 3.26 (m, 1 H) 4.16 (t, J = 4.93 Hz, 1H) a]pyridin-7- 4.23-4.34 (m, 2 H) 7.34 (dd, J = 7.14, 1.82 Hz, 1 H)7.55 (d, yl)benzamide J = 8.04 Hz, 1 H) 7.65 (d, J = 1.04 Hz, 1 H) 7.87(dd, J = 8.04, 1.82 Hz, 1 H) 7.95-8.04 (m, 3 H) 8.65 (dd, J = 7.14, 0.78Hz, 1 H) 8.84 (d, J = 5.97 Hz, 1 H) 20-56 2-chloro-N-((1R,2R,4S)- 392.01H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (t, J = 7.07 Hz, 1 H) 7-cyano-7-1.39 (dd, J = 12.72, 4.15 Hz, 1 H) 1.57-1.64 (m, 1 H)azabicyclo[2.2.1]heptan- 1.69-1.86 (m, 2 H) 1.97-2.04 (m, 2 H) 2.19-2-yl)-4-(imidazo[1,5- 2.27 (m, 1 H) 3.31 (s, 4 H) 4.03 (q, a]pyridin-6-J = 7.14 Hz, 1 H) 4.16 (t, J = 4.87 Hz, 1 H) 4.25-4.32 (m, 2 H)yl)benzamide 7.18 (dd, J = 9.47, 1.56 Hz, 1 H) 7.41 (s, 1 H) 7.56 (d, J= 8.04 Hz, 1 H) 7.67 (d, J = 9.47 Hz, 1 H) 7.74 (dd, J = 8.04, 1.82 Hz,1 H) 7.87 (d, J = 1.69 Hz, 1 H) 8.40 (s, 1 H) 8.83 (d, J = 5.97 Hz, 1 H)8.85 (d, J = 1.30 Hz, 1 H) 20-57 2-chloro-N-((1R,2R,4S)- 356.0 1H NMR(500 MHz, DMSO-d6) δ ppm 1.39 (dd, J = 12.85, 4.02 7-cyano-7- Hz, 4 H)1.57-1.63 (m, 4 H) 1.67- azabicyclo[2.2.1]heptan- 1.75 (m, 4 H)1.77-1.85 (m, 4 H) 1.97-2.03 (m, 4 H) 2.18- 2-yl)-4-(1-methyl-1H- 2.25(m, 4 H) 3.01 (s, 1 H) 3.31 (s, 15 H) pyrazol-3-yl)benzamide 3.58 (s, 1H) 3.90 (s, 13 H) 4.15 (t, J = 4.93 Hz, 4 H) 4.23- 4.30 (m, 8 H) 6.83(d, J = 2.34 Hz, 4 H) 7.30 (d, J = 2.21 Hz, 1 H) 7.46 (d, J = 8.04 Hz, 7H) 7.74-7.89 (m, 14 H) 8.79 (d, J = 5.84 Hz, 4 H) 20-582-chloro-N-((1R,2R,4S)- 356.0 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (t, J= 7.14 Hz, 2 H) 7-cyano-7- 1.38 (dd, J = 12.72, 4.15 Hz, 4 H) 1.53-1.66(m, 4 H) azabicyclo[2.2.1]heptan- 1.68-1.77 (m, 4 H) 1.78-1.87 (m, 4 H)1.93-2.07 (m, 5 H) 2-yl)-4-(1-methyl-1H- 2.18-2.27 (m, 4 H) 2.82pyrazol-5-yl)benzamide (s, 1 H) 3.03 (s, 1 H) 3.31 (s, 8 H) 3.88 (s, 12H) 4.03 (d, J = 7.14 Hz, 1 H) 4.16 (t, J = 4.93 Hz, 4 H) 4.23-4.33 (m, 8H) 6.51 (d, J = 1.95 Hz, 4 H) 7.50 (d, J = 1.82 Hz, 5 H) 7.53-7.61 (m, 9H) 7.69-7.72 (m, 4 H) 8.86 (d, J = 5.97 Hz, 4 H) 20-592-chloro-N-((1R,2R,4S)- 382.0 1H NMR (500 MHz, DMSO-d6) δ ppm 0.85 (s, 1H) 0.92-1.10 7-cyano-7- (m, 17 H) 1.17 (t, J = 7.07 Hz, 4 H)azabicyclo[2.2.1]heptan- 1.39 (dd, J = 12.78, 3.96 Hz, 3 H) 1.54-1.65(m, 3 H) 1.67-1.76 2-yl)-4-(1-cyclopropyl- (m, 3 H) 1.76-1.86 (m, 3 H)1.94- 1H-pyrazol-4- 2.04 (m, 6 H) 2.11-2.25 (m, 3 H) 3.32 (s, 4 H)3.65-3.80 (m, 4 yl)benzamide H) 4.03 (q, J = 7.14 Hz, 2 H) 4.14 (t, J =4.87 Hz, 3 H) 4.21-4.31 (m, 6 H) 7.41 (d, J = 8.04 Hz, 3 H) 7.52 (br s,1 H) 7.55-7.65 (m, 5 H) 7.76 (d, J = 1.56 Hz, 3 H) 7.90 (s, 1 H)7.96-8.00 (m, 3 H) 8.35- 8.41 (m, 3 H) 8.74 (br d, J = 5.71 Hz, 3 H)20-60 2-chloro-N-((1R,2R,4S)- 381.0 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17(t, J = 7.07 Hz, 2 H) 7-cyano-7- 1.39 (dd, J = 12.78, 3.96 Hz, 3 H)1.54-1.66 (m, 3 H) azabicyclo[2.2.1]heptan- 1.67-1.76 (m, 3 H) 1.76-1.86(m, 3 H) 1.92-2.07 2-yl)-4-(1- (m, 5 H) 2.11-2.26 (m, 3 H) 3.32(cyanomethyl)-1H- (s, 2 H) 4.03 (q, J = 7.14 Hz, 1 H) 4.15 (t, J = 4.93Hz, 3 H) pyrazol-4-yl)benzamide 4.21-4.32 (m, 6 H) 5.53 (s, 6 H) 5.75(s, 1 H) 7.45 (d, J = 7.91 Hz, 3 H) 7.64 (dd, J = 7.98, 1.62 Hz, 3 H)7.80 (d, J = 1.56 Hz, 3 H) 8.18 (s, 3 H) 8.43 (s, 3 H) 8.76 (br d, J =5.84 Hz, 3 H) 20-61 2-chloro-N-((1R,2R,4S)- 356.0 1H NMR (500 MHz,DMSO-d6) δ ppm 1.38 (d, J = 4.28 Hz, 2 H) 7-cyano-7- 1.40 (d, J = 3.76Hz, 2 H) 1.57-1.63 azabicyclo[2.2.1]heptan- (m, 4 H) 1.70-1.74 (m, 3 H)1.80 (td, J = 7.75, 4.09 Hz, 3 H) 2-yl)-4-(1-methyl-1H- 2.00 (ddd, J =12.75, 8.99, 4.09 Hz, 4 H) imidazol-4-ypbenzamide 2.21 (br s, 2 H)3.29-3.33 (m, 31 H) 3.64 (s, 1 H) 3.69 (s, 13 H) 4.14 (t, J = 4.87 Hz, 4H) 4.24-4.28 (m, 8 H) 7.42 (d, J = 7.91 Hz, 4 H) 7.68 (s, 4 H) 7.74 (dd,J = 7.91, 1.56 Hz, 4 H) 7.78 (d, J = 1.17 Hz, 4 H) 7.83 (d, J = 1.43 Hz,4 H) 8.73 (d, J = 5.84 Hz, 4 H) 20-62 2-chloro-N-((1R,2R,4S)- 356.0 1HNMR (500 MHz, DMSO-d6) δ ppm 1.39 (dd, J = 12.78, 3.96 7-cyano-7- Hz, 1H) 1.54-1.65 (m, 1 H) 1.67- azabicyclo[2.2.1]heptan- 1.76 (m, 1 H)1.76-1.86 (m, 1 H) 1.91-2.08 (m, 1 H) 2.16- 2-yl)-4-(1-methyl-1H- 2.26(m, 1 H) 3.32 (s, 1 H) 3.86 (s, 3 H) pyrazol-4-yl)benzamide 4.14 (t, J =4.93 Hz, 1 H) 4.21-4.30 (m, 2 H) 7.42 (d, J = 7.91 Hz, 1 H) 7.59 (dd, J= 7.98, 1.62 Hz, 1 H) 7.74 (d, J = 1.56 Hz, 1 H) 7.98 (s, 1 H) 8.28 (s,1 H) 8.73 (br d, J = 5.71 Hz, 1 H) 20-63 N-((1R,2R,4S)-7-cyano- 416.2 1HNMR (600 MHz, DMSO-d6) δ ppm 0.06-0.09 (m, 1 H) 7- 0.96-1.03 (m, 6 H)1.59 (dd, J = 12.81, azabicyclo[2.2.1]heptan- 4.55 Hz, 1 H) 1.64-1.74(m, 2 H) 1.79-1.90 (m, 2H) 2.07 (dt, 2-yl)-4-(4-cyano-2- J = 13.12, 6.52Hz, 1 H) 2.36-2.47 pyridinyl)-3-(2- (m, 2 H) 3.20 (br s, 1 H) 3.25-3.30(m, 2H) 3.97 (d, J = 6.15 Hz, methylpropoxy)benzamide 2 H) 4.18 (t, J =4.83 Hz, 1 H) 4.23-4.33 (m, 2 H) 7.38 (s, 1 H) 7.56 (d, J = 1.48 Hz, 1H) 7.61 (dd, J = 8.02, 1.56 Hz, 1 H) 7.85 (dd, J = 4.98, 1.48 Hz, 1 H)7.91 (d, J = 8.02 Hz, 1 H) 8.30-8.33 (m, 1 H) 8.68 (d, J = 5.92 Hz, 1 H)8.95 (dd, J = 4.98, 0.93 Hz, 1H) 20-64 N-((1R,2R,4S)-7-cyano- 406.0 1HNMR (500 MHz, CHLOROFORM-d) δ ppm 1.04 (d, J = 6.75 7- Hz, 17 H) 1.09(br d, J = 6.75 Hz, 1 H) azobicyclo[2.2.1]heptan- 1.19 (dd, J = 13.10,3.89 Hz, 4 H) 1.34-1.48 (m, 2 H) 1.62-1.75 2-yl)-3-(2- (m, 5 H)1.87-2.02 (m, 6 H) 2.05-2.20 (m, 6 H) methylpropoxy)-4-(5- 2.56-2.65 (m,11 H) 3.51 (s, 3 H) 3.92 (s, 3 H) methyl-2- 3.93 (s, 3 H) 4.13 (t, J =5.00 Hz, 3 H) pyrazinyl)benzamide 4.46-4.57 (m, 6 H) 6.18 (br d, J =3.63 Hz, 3 H) 7.29-7.39 (m, 5 H) 7.48 (s, 2 H) 7.52-7.64 (m, 4 H) 7.95(d, J = 7.91 Hz, 3 H) 8.56 (s, 3 H) 9.17 (d, J = 1.30 Hz, 3 H) 20-65N-((1R,2R,4S)-7-cyano- 405.2 1H NMR (600 MHz, DMSO-d6) δ ppm 0.06-0.09(m, 1 H) 7- 0.94-1.00 (m, 6 H) 1.24 (br s, 1 H) 1.59azabicyclo[2.2.1]heptan- (dd, J = 12.69, 4.59 Hz, 1 H) 1.65-1.75 (m, 2H) 1.79-1.90 (m, 2-yl)-3-(2- 2 H) 2.02 (dt, J = 13.22, 6.51 Hz, 1 H)methylpropoxy)-4-(6- 2.16-2.26 (m, 1 H) 2.36-2.47 (m, 1 H) 2.52-2.54 (m,3 H) methyl-2- 2.58-2.67 (m, 1 H) 3.17 (br s, 1 H) pyridinyl)benzamide3.90 (d, J = 6.23 Hz, 2 H) 4.18 (br t, J = 4.79 Hz, 1 H) 4.23-4.32 (m, 2H) 7.21 (d, J = 7.47 Hz, 1 H) 7.34-7.46 (m, 1 H) 7.51 (d, J = 1.56 Hz, 1H) 7.56 (dd, J = 7.98, 1.60 Hz, 1 H) 7.67-7.71 (m, 1 H) 7.71-7.75 (m,1H) 7.81 (d, J = 7.94 Hz, 1 H) 8.63 (br d, J = 5.45 Hz, 1 H) 20-66N-((1R,2R,4S)-7-cyano- 406.2 1H NMR (600 MHz, DMSO-d6) δ ppm 0.91 (d, J= 6.70 Hz, 6 H) 7- 1.59 (dd, J = 12.81, 4.63 Hz, 1 H) 1.65-1.75azabicyclo[2.2.1]heptan- (m, 2 H) 1.83 (br dd, J = 7.51, 4.63 Hz, 1 H)1.85-1.94 (m, 2-yl)-3-(2- 2 H) 2.19-2.27 (m, 1 H) 2.36-2.47methylpropoxy)-4-(4- (m, 1 H) 2.52-2.57 (m, 1 H) 3.84 (d, J = 6.23 Hz, 2H) 4.18 (t, methyl-2- J = 4.83 Hz, 1 H) 4.25-4.33 (m, 2 H)pyrimidinyl)benzamide 7.34 (d, J = 5.14 Hz, 1 H) 7.50 (d, J = 1.48 Hz, 1H) 7.55 (dd, J = 7.86, 1.48 Hz, 1 H) 7.62 (d, J = 7.86 Hz, 1 H) 8.64 (d,J = 5.84 Hz, 1 H) 8.73 (d, J = 5.06 Hz, 1 H) 20-67N-((1R,2R,4S)-7-cyano- 430.0 1H NMR (500 MHz, DMSO-d6) δ ppm 0.97 (d, J= 6.75 Hz, 6 H) 7- 1.07 (s, 3 H) 1.59 (dd, J = 12.72, 4.54 Hz, 1 H)azabicyclo[2.2.1]heptan- 1.65-1.74 (m, 2 H) 1.79-1.91 (m, 2 H) 1.98-2.092-yl)-4-(6- (m, 1 H) 2.19-2.27 (m, 1 H) 3.31 (s, 16 (cyanomethyl)-2- H)3.90-3.94 (m, 2 H) 4.18 (t, J = 4.74 Hz, 1 H) 4.25-4.32 (m, 4pyridinyl)-3-(2- H) 5.75 (s, 1 H) 7.39 (dd, J = 6.49,methylpropoxy)benzamide 2.08 Hz, 1 H) 7.53 (d, J = 1.43 Hz, 1 H) 7.59(dd, J = 7.98, 1.49 Hz, 1 H) 7.84-7.92 (m, 3 H) 8.63 (d, J = 5.71 Hz, 1H) 20-68 N-((1R,2R,4S)-7-cyano- 394.0 1H NMR (500 MHz, DMSO-d6) δ ppm1.05 (d, J = 6.75 Hz, 14 7- H) 1.17 (t, J = 7.14 Hz, 2 H) 1.59 (dd,azabicyclo[2.2.1]heptan- J = 12.65, 4.48 Hz, 2 H) 1.65-1.73 (m, 4 H)1.78-1.90 (m, 5 H) 2-yl)-3-(2- 1.99 (s, 2 H) 2.10-2.25 (m, 4 H)methylpropoxy)-4-(1- 3.31 (s, 6 H) 3.57 (s, 1 H) 3.72 (s, 1 H) 3.87-3.93(m, 11 H) methyl-1H-pyrazol-3- 4.03 (q, J = 7.14 Hz, 1 H) 4.15-4.18 (m,yl)benzamide 2 H) 4.24-4.31 (m, 4 H) 5.75 (s, 1 H) 6.81 (d, J = 2.21 Hz,2 H) 6.90 (d, J = 8.69 Hz, 1 H) 7.27 (d, J = 8.56 Hz, 1 H) 7.43-7.52 (m,5 H) 7.74 (d, J = 2.08 Hz, 2 H) 7.98 (s, 1 H) 7.98-8.01 (m, 1 H) 8.55(br d, J = 5.58 Hz, 2 H) 20-69 N-((1R,2R,4S)-7-cyano- 394.0 1H NMR (500MHz, DMSO-d6) δ ppm 0.87 (d, J = 6.62 Hz, 6 H) 7- 1.17 (t, J = 7.14 Hz,2 H) 1.58 (dd, azabicyclo[2.2.1]heptan- J = 12.72, 4.41 Hz, 1 H)1.64-1.74 (m, 2 H) 1.81-2.00 (m, 5 H) 2-yl)-3-(2- 2.18-2.28 (m, 1 H)3.31 (s, 3 H) methylpropoxy)-4-(1- 3.65 (s, 3 H) 3.77-3.89 (m, 2 H) 4.03(q, J = 7.14 Hz, 1 H) methyl-1H-pyrazol-5- 4.14-4.22 (m, 1 H) 4.24-4.33(m, 2 H) yl)benzamide 5.75 (s, 1 H) 6.29 (d, J = 1.69 Hz, 1 H) 7.39 (d,J = 7.78 Hz, 1 H) 7.44-7.58 (m, 3 H) 8.63 (br d, J = 5.58 Hz, 1 H) 20-70N-((1R,2R,4S)-7-cyano- 394.0 1H NMR (500 MHz, DMSO-d6) δ ppm 1.03 (br d,J = 6.62 Hz, 7- 6 H) 1.23 (br s, 1 H) 1.55 (br dd,azabicyclo[2.2.1]heptan- J = 12.65, 4.09 Hz, 1 H) 1.62-1.73 (m, 2 H)1.77-1.88 (m, 2 H) 2-yl)-4-(1-methyl-1H- 2.07 (dt, J = 13.10, 6.55 Hz, 1H) 2.21 imidazol-4-yl)-3-(2- (br t, J = 10.57 Hz, 1 H) 3.38 (br dd, J =13.82, 6.94 Hz, 1 H) methylpropoxy)benzamide 3.49-3.68 (m, 1 H) 3.90 (brd, J = 6.23 Hz, 2 H) 4.16 (br t, J = 4.54 Hz, 1 H) 4.21-4.30 (m, 2 H)4.41 (s, 2 H) 6.87 (m, J = 8.43 Hz, 2 H) 7.22 (m, J = 8.43 Hz, 2 H) 7.40(d, J = 8.22 Hz, 1 H) 7.45 (s, 1 H) d, J = 8.17 Hz, 1 H) 8.60 (br d, J =5.19 Hz, 1 H) 20-71 N-((1R,2R,4S)-7-cyano- 416.0 1H NMR (500 MHz,DMSO-d6) δ ppm 0.97 (d, J = 6.75 Hz, 7- 6 H) 1.07 (s, 3 H) 1.59 (dd, J =12.72, 4.54 azabicyclo[2.2.1]heptan- Hz, 1 H) 1.65-1.74 (m, 2 H)1.79-1.91 (m, 2 H) 1.98-2.09 2-yl)-4-(6-cyano-2- (m, 1 H) 2.19-2.27 (m,1 H) 3.31 (s, 16 pyridinyl)-3-(2- H) 3.90-3.94 (m, 2 H) 4.18 (t, J =4.74 Hz, 1 H) 4.25-4.32 (m, 4 methylpropoxy)benzamide H) 5.75 (s, 1 H)7.39 (dd, J = 6.49, 2.08 Hz, 1 H) 7.53 (d, J = 1.43 Hz, 1 H) 7.59 (dd, J= 7.98, 1.49 Hz, 1 H) 7.84-7.92 (m, 3 H) 8.63 (d, J = 5.71 Hz, 1 H)20-72 N-((1R,2R,4S)-7-cyano- 406.0 7- azabicyclo[2.2.1]heptan-2-yl)-3-(2- methylpropoxy)-4-(6- methyl-3- pyridazinyl)benzamide 20-73N-((1R,2R,4S)-7-cyano- 406.0 1H NMR (600 MHz, DMSO-d6) δ ppm 0.99 (d, J= 6.79 Hz, 6 H) 7- 1.55-1.63 (m, 1 H) 1.66-1.74 (m, 2azabicyclo[2.2.1]heptan- H) 1.80-1.91 (m, 2 H) 2.07 (dquin, J = 13.20,6.60, 6.60, 6.60, 2-yl)-3-(2- 6.60 Hz, 1 H) 219-2.29 (m, 1 H) 2.52-2.58methylpropoxy)-4-(2- (m, 1 H) 2.66-2.70 (m, 3 H) 3.26-3.28 (m, 1 H)3.32-3.42 methyl-4- (m, 2 H) 3.95 (d, J = 6.24 Hz, 2 H) 4.18pyrimidinyl)benzamide (t, J = 4.86 Hz, 1 H) 4.26-4.33 (m, 2 H) 7.54 (d,J = 1.47 Hz, 1 H) 7.59 (dd, J = 7.98, 1.56 Hz, 1 H) 7.81 (d, J = 5.32Hz, 1 H) 7.96 (d, J = 7.89 Hz, 1 H) 8.66 (d, J = 5.69 Hz, 1 H) 8.74 (d,J = 5.32 Hz, 1 H) 20-74 N-((1R,2R,4S)-7-cyano- 408.2 1H NMR (600 MHz,DMSO-d6) δ ppm 0.94 (t, J = 7.47 Hz, 3 H) 7- 1.04 (d, J = 6.70 Hz, 3 H)1.23-1.35 azabicyclo[2.2.1]heptan- (m, 1 H) 1.53-1.61 (m, 2 H) 1.64-1.73(m, 2 H) 1.78-1.88 2-yl)-3-(2- (m, 2 H) 1.92-2.00 (m, 1 H) 2.17-2.25methylbutoxy)-4-(1- (m, 1 H) 3.24-3.30 (m, 1 H) 3.88 (s, 3 H) 3.93 (dd,J = 9.19, 6.46 methyl-1H-pyrazol-4- Hz, 1 H) 4.01 (dd, J = 9.19, 5.68Hz, yl)benzamide 1 H) 4.17 (t, J = 4.87 Hz, 1 H) 4.23-4.31 (m, 2 H) 7.45(d, J = 1.64 Hz, 1 H) 7.49 (dd, J = 8.02, 1.63 Hz, 1 H) 7.68 (d, J =8.02 Hz, 1 H) 7.97 (d, J = 0.62 Hz, 1 H) 8.15 (s, 1 H) 8.51 (d, J = 5.76Hz, 1 H) 20-75 N-((1R,2R,4S)-7-cyano- 408.0 1H NMR (600 MHz, DMSO-d6) δppm 1.05 (dd, J = 6.73, 0.90 7- Hz, 6 H) 1.40 (t, J = 7.28 Hz, 3 H) 1.58azabicyclo[2.2.1]heptan- (dd, J = 12.69, 4.67 Hz, 1 H) 1.63-1.75 (m, 2H) 1.78-1.89 (m, 2-yl)-4-(1-ethyl-1H- 2 H) 2.14-2.25 (m, 2 H) 3.16-3.26pyrazol-4-yl)-3-(2- (m, 1 H) 3.92 (d, J = 6.31 Hz, 2 H) 4.13-4.22 (m, 3H) methylpropoxy)benzamide 4.22-4.31 (m, 2 H) 7.45 (d, J = 1.63 Hz, 1 H)7.49 (dd, J = 8.02, 1.63 Hz, 1 H) 7.70 (d, J = 8.02 Hz, 1 H) 7.99 (d, J= 0.62 Hz, 1 H) 8.21 (s, 1 H) 8.51 (d, J = 5.76 Hz, 1 H) 20-76N-((1R,2R,4S)-7-cyano- 420.0 1H NMR (600 MHz, DMSO-d6) δ ppm 0.98-1.09(m, 10 H) 7- 1.58 (dd, J = 12.73, 4.63 Hz, 1 H) 1.64-1.74 (m, 2H)azabicyclo[2.2.1]heptan- 1.78-1.88 (m, 2H) 2.14-2.24 (m, 2 H) 3.16-3.29(m, 1 H) 2-yl)-4-(1-cyclopropyl- 3.77 (tt, J = 7.36, 3.78 Hz, 1 H) 3.92(d, J = 6.31 Hz, 2 H) 1H-pyrazol-4-yl)-3-(2- 4.17 (t, J = 4.83 Hz, 1 H)4.22-4.31 (m, 2 H) 7.45 (d, J = 1.63 Hz, methylpropoxy)benzamide 1 H)7.49 (dd, J = 8.02, 1.64 Hz, 1 H) 7.71 (d, J = 8.02 Hz, 1 H) 7.99 (d, J= 0.62 Hz, 1 H) 8.23 (s, 1 H) 8.51 (d, J = 5.76 Hz, 1 H) 22-1N-((1R,2R,4S)-7-cyano- 1H NMR (600 MHz, DMSO-d6) δ: 9.61 (s, 1H), 8.85(d, J = 5.8 7- Hz, 1H) 8.74 (s, 1H), 8.19 (s, 1H), 8.01-8.08 (m, 2H),7.46 (d, azabicyclo[2.2.1]heptan- J = 7.3 Hz, 1H), 4.31-4.36 (m, 1H),4.29 (t, J = 4.4 Hz, 1H), 4.19 2-yl)-1-(6-methyl-2- (t, J = 4.9 Hz, 1H),2.62 (s, 3H), 2.21-2.30 (m, 1H), 1.89-1.96 pyridinyl)-7- (m, 1H),1.80-1.89 (m, 1H), 1.66-1.76 (m, 2H), 1.59 (dd, J =(trifluoromethyl)-1H- 12.7, 4.6 Hz, 1H) indazole-5-carboxamide 23-1N-((1R,2R,4S)-7-cyano- [M + 1] 7- 379.2 azabicyclo[2.2.1]heptan-2-yl)-2-(2,3- dichlorophenyl)-1- pyrrolidinecarboxamide 23-22-(3-bromo-2- [M + 1] methylphenyl)-N- 403.2 ((1R,2R,4S)-7-cyano-7-azabicyclo[2.2.1]heptan- 2-yl)-1- pyrrolidinecarboxamide 23-3N-((1R,2R,4S)-7-cyano- [M + 1] 7- 365.1 azabicyclo[2.2.1]heptan-2-yl)-2-(2,3- dichlorophenyl)-1- azetidinecarboxamide 23-41-((1R,2R,4S)-7-cyano- [M + 1] 7- 353.3 azabicyclo[2.2.1]heptan-2-yl)-3-((3-(2- propanyl)-2,3-dihydro- 1H-inden-1- yl)methyl)urea 23-51-((1R,2R,4S)-7-cyano- [M + 1] 7- 353.1 azabicyclo[2.2.1]heptan-2-yl)-3-(1-(2,3- dichlorophenyl)ethyl)urea 23-6 1-((7-chloro-1,2,3,4-[M + 1] tetrahydro-1- 359.2 naphthalenyl)methyl)-3-((1R,2R,4S)-7-cyano-7- azabicyclo[2.2.1]heptan- 2-yl)urea 23-71-((1R,2R,4S)-7-cyano- [M + 1] 7- 353.3 azabicyclo[2.2.1]heptan-2-yl)-3-(2-(2,5- dichlorophenyl)ethyl)urea 23-8 7-chloro-N-((1R,2R,4S)-[M + 1] 7-cyano-7- 347.3 azabicyclo[2.2.1]heptan- 2yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)- carboxamide 23-9 8-chloro-N-(1R,2R,4S)- [M + 1]7-cyano-7- 370.2 azabicyclo[2.2.1]heptan- 2-yl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole 2-carboxamide 24-1 N′-((1R,2R,4S)-7-cyano- [M +1] 7- 401.3 azabicyclo[2.2.1]heptan- 2-yl)-N-(2- hydroxyethyl)-N-(tricyclo[3.3.1.1~3,7~]decan- 1-ylmethyl)ethanediamide 25-12-chloro-N-((1R,2R,4S)- 410.0 H NMR (600 MHz, DMSO-d6) δ ppm 1.38 (dd, J= 12.67, 4.13 7-cyano-7- Hz, 1 H) 1.55-1.65 (m, 1 H) 1.68-1.77 (m, 1 H)azabicyclo[2.2.1]heptan- 1.78-1.86 (m, 1 H) 2.00 (ddd, J = 12.90, 8.99,4.18 2-yl)-4-(4- Hz, 1 H) 2.19-2.27 (m, 1 H) 3.16-3.28 (m, 1 H) 4.16(trifluoromethyl)-1H- (t, J = 5.04 Hz, 1 H) 4.24-4.31 (m, 2 H) 7.64 (d,J = 8.36 Hz, pyrazol-1-yl)benzamide 1 H) 7.96 (dd, J = 8.36, 2.18 Hz, 1H) 8.11 (d, J = 2.18 Hz, 1 H) 8.28 (s, 1 H) 8.86 (br d, J = 5.90 Hz, 1H) 9.33 (s, 1 H) 25-2 2-chloro-N-((1R,2R,4S)- 381.0 7-cyano-7-azabicyclo[2.2.1]heptan- 2-yl)-4-(4- (cyanomethyl)-1H-pyrazol-1-yl)benzamide 25-3 2-chloro-N-((1R,2R,4S)- 370.0 1H NMR (600MHz, DMSO-d6) δ ppm 1.21 (t, J = 7.58 Hz, 3 H) 7-cyano-7- 1.24 (br s, 1H) 1.39 (dd, J = 12.67, 4.13 Hz, 1 H) 1.56-1.65 azabicyclo[2.2.1]heptan-(m, 1 H) 1.73 (br d, J = 12.35 Hz, 1 H) 1.77-1.87 (m, 1 H)2-yl)-4-(4-ethyl-1H- 2.00 (ddd, J = 12.90, 9.13, 4.13 Hz, 1 H) 2.22 (brs, 1 H) pyrazol-1-yl)benzamide 2.51-2.55 (m, 2 H) 3.19 (br s, 1 H)3.23-3.29 (m, 4 H) 3.35-3.46 (m, 3 H) 4.15 (t, J = 5.04 Hz, 1 H)4.23-4.30 (m, 2 H) 7.56 (d, J = 8.36 Hz, 1 H) 7.67 (s, 1 H) 7.85 (dd, J= 8.40, 2.13 Hz, 1 H) 7.97 (d, J = 2.09 Hz, 1 H) 8.43 (s, 1 H) 8.79 (brd, J = 5.90 Hz, 1 H) 26- (3R)-1-(3-chlorophenyl)- 358.8 1H NMR (500 MHz,CHLOROFORM-d) Shift 7.67 (t, J = 2.01 1-1 N-((1R,2R,4S)-7-cyano- Hz,1H), 7.46-7.52 (m, 1H), 7.29-7.34 (m, 1H), 7.14-7.19 (m, 7- 1H), 6.06(br s, 1H), 4.36 (br s, 1H), 4.04-4.17 (m, 2H), 3.87-azabicyclo[2.2.1]heptan- 4.01 (m, 1H), 3.16-3.28 (m, 1H), 2.79-2.96 (m,2H), 2.41-2.52 2-yl)-5-oxo-3- (m, 1H), 2.01-2.13 (m, 1H), 1.94 (dt, J =2.40, 12.75 Hz, 1H), pyrrolidinecarboxamide 1.82 (ddd, J = 4.54, 8.89,13.30 Hz, 2H), 1.60 (ddd, J = 4.22, 8.76, 12.59 Hz, 1H), 1.08-1.19 (m,1H) 26- (3S)-1-(3-chlorophenyl)- 358.8 1H NMR (500 MHz, CHLOROFORM-d)Shift 7.67 (t, J = 2.08 2-1 N-((1R,2R,4S)-7-cyano- Hz, 1H), 7.45-7.50(m, 1H), 7.31 (t, J = 8.11 Hz, 1H), 7.17 (ddd, 7- J = 0.84, 1.91, 8.01Hz, 1H), 6.26 (br d, J = 4.15 Hz, 1H), 4.32- azabicyclo[2.2.1]heptan-4.39 (m, 2H), 4.06-4.15 (m, 2H), 3.95 (t, J = 9.08 Hz, 1H), 3.212-yl)-5-oxo-3- (quin, J = 8.50 Hz, 1H), 2.92 (dd, J = 8.63, 17.06 Hz,1H), 2.81 pyrrolidinecarboxamide (dd, J = 9.47, 17.00 Hz, 1H), 2.40-2.51(m, 1H), 2.00-2.10 (m, 1H), 1.79-1.96 (m, 3H), 1.59 (ddd, J = 4.22,8.66, 12.55 Hz, 1H), 1.12 (dd, J = 3.96, 12.91 Hz, 1H) 26-3(3S)-1-(3-chlorophenyl)- 345 1H NMR (600 MHz, DMSO-d6) Shift 8.29 (br d,J = 5.76 Hz, N-((1R,2R,4S)-7-cyano- 1H), 7.15 (t, J = 8.10 Hz, 1H), 6.60(br d, J = 7.79 Hz, 1H), 6.46- 7- 6.53 (m, 2H), 4.07-4.17 (m, 3H),3.40-3.46 (m, 1H), 3.19-3.36 azabicyclo[2.2.1]heptan- (m, 3H), 3.03-3.18(m, 1H), 2.14-2.22 (m, 2H), 2.00-2.14 (m, 2-yl)-3- 1H), 1.75-1.90 (m,2H), 1.54-1.71 (m, 2H), 1.22-1.31 (m, 1H) pyrrolidinecarboxamide 26-4(3R)-1-(3-chlorophenyl)- 345 1H NMR (600 MHz, DMSO-d6) Shift 8.29 (br d,J = 5.29 Hz, N-((1R,2R,4S)-7-cyano- 1H), 7.15 (t, J = 8.02 Hz, 1H), 6.60(br d, J = 7.63 Hz, 1H), 6.52 (s, 7- 1H), 6.48 (d, J = 8.61 Hz, 1H),4.07-4.16 (m, 3H), 3.46 (br t, azabicyclo[2.2.1]heptan- J = 8.72 Hz,1H), 3.20-3.36 (m, 3H), 3.10 (quin, J = 7.55 Hz, 1H), 2-yl)-3- 2.17 (brdd, J = 4.52, 11.83 Hz, 2H), 2.03-2.13 (m, 1H), 1.76-1.90pyrrolidinecarboxamide (m, 2H), 1.63-1.70 (m, 1H), 1.51-1.63 (m, 1H),1.26 (br dd, J = 3.66, 12.69 Hz, 1H) 26-5 (2S)-5-bromo-N- 359.8 1H NMR(600 MHz, DMSO-d6) Shift 8.23 (br d, J = 5.61 Hz, ((1R,2R,4S)-7-cyano-7-1H), 7.40 (s, 1H), 7.30 (br d, J = 7.94 Hz, 1H), 7.16 (d, J = 7.94azabicyclo[2.2.1]heptan- Hz, 1H), 4.08-4.15 (m, 3H), 3.19-3.26 (m, 1H),3.03-3.12 (m, 2-yl)-2,3-dihydro-1H- 3H), 2.93-3.01 (m, 1H), 2.18 (br s,1H), 1.77-1.88 (m, 2H), 1.55- indene-2-carboxamide 1.70 (m, 2H),1.21-1.32 (m, 1H) 26-6 (2R)-5-bromo-N- 359.8 1H NMR (600 MHz, DMSO-d6)Shift 8.23 (br d, J = 5.61 Hz, ((1R,2R,4S)-7-cyano-7- 1H), 7.40 (s, 1H),7.30 (br d, J = 7.94 Hz, 1H), 7.16 (d, J = 7.94 azabicyclo[2.2.1]heptan-Hz, 1H), 4.08-4.15 (m, 3H), 3.19-3.26 (m, 1H), 3.03-3.12 (m,2-yl)-2,3-dihydro-1H- 3H), 2.93-3.01 (m, 1H), 2.18 (br s, 1H), 1.77-1.88(m, 2H), 1.55- indene-2-carboxamide 1.70 (m, 2H), 1.21-1.32 (m, 1H) 27-1(3R)-N-((1R,2R,4S)-7- 353 1H NMR (600 MHz, DMSO-d6) Shift 8.29 (br d, J= 6.15 Hz, cyano-7- 1H), 8.09 (d, J = 4.98 Hz, 1H), 6.52 (d, J = 5.06Hz, 1H), 4.06-4.16 azabicyclo[2.2.1]heptan- (m, 2H), 3.66 (dd, J = 7.94,10.98 Hz, 1H), 3.51-3.60 (m, 1H), 2-yl)-1-(4-cyclopropyl- 3.34-3.49 (m,3H), 3.04 (quin, J = 7.55 Hz, 1H), 2.07-2.22 (m, 2--pyrimidinyl)-3- 2H,2.01 (qd, J = 8.16, 12.27 Hz, 1H), 1.76-1.92 (m, 3H), 1.55-pyrrolidinecarboxamide 1.71 (m, 2H), 1.20-1.33 (m, 1H), 0.90-1.00 (m,4H) 27-2 (3R)-N-((1R,2R,4S)-7- 380 1H NMR (600 MHz, DMSO-d6) Shift 8.34(br d, J = 5.99 Hz, cycano-7- 1H), 7.69 (t, J = 7.90 Hz, 1H), 6.96 (d, J= 7.24 Hz, 1H), 6.73 (d, azabicyclo[2.2.1]heptan- J = 8.56 Hz, 1H),4.07-4.17 (m, 3H), 3.64 (br t, J = 9.07 Hz, 1H), 2-yl)-1-(6- 3.50-3.58(m, 1H), 3.36-3.49 (m, 2H), 3.11 (quin, J = 7.47 Hz,(trifluoromethyl)-2- 1H), 2.14-2.24 (m, 2H), 2.03-2.13 (m, 1H),1.77-1.88 (m, 2H), pyridinyl)-3- 1.56-1.70 (m, 2H), 1.27 (dd, J = 4.44,12.69 Hz, 1H) pyrrolidinecarboxamide 27-3 (3S)-N-((1R,2R,4S)-7- 380 1HNMR (600 MHz, DMSO-d6) Shift 8.34 (br d, J = 5.99 Hz, cyano-7- 1H), 7.69(t, J = 7.90 Hz, 1H), 6.96 (d, J = 7.24 Hz, 1H), 6.73 (d,azabicyclo[2.2.1]heptan- J = 8.56 Hz, 1H), 4.07-4.17 (m, 3H), 3.64 (brt, J = 9.07 Hz, 1H), 2-yl)-1-(6- 3.50-3.58 (m, 1H), 3.36-3.49 (m, 2H),3.11 (quin, J = 7.47 Hz, (trifluromethyl)-2- 1H), 2.14-2.24 (m, 2H),2.03-2.13 (m, 1H), 1.77-1.88 (m, 2H), pyridinyl)-3- 1.56-1.70 (m, 2H),1.27 (dd, J = 4.44, 12.69 Hz, 1H) pyrrolidinecarboxamide 28-1(3S)-N-((1R,2R,4S)-7- 379 1H NMR (500 MHz, CHLOROFORM-d) Shift 6.69 (t,J = 1.69 cyano-7- Hz, 1H), 6.42 (d, J = 1.69 Hz, 2H), 5.79 (br d, J =4.54 Hz, 1H), azabicyclo[2.2.1]heptan- 4.29-4.40 (m, 2H), 4.07 (t, J =4.93 Hz, 1H), 3.44-3.52 (m, 3H), 2-yl)-1-(3,5- 3.27-3.39 (m, 1H), 3.04(quin, J = 7.66 Hz, 1H), 2.43-2.51 (m, dichlorophenyl)-3- 1H), 2.24-2.35(m, 2H), 2.03-2.12 (m, 1H), 1.87-1.98 (m, 1H), pyrrolidinecarboxamide1.79-1.85 (m, 1H), 1.54-1.61 (m, 1H), 1.05 (dd, J = 4.09, 12.78 Hz, 1H)28-2 (3S)-1-(5-chloro-2- 370 1H NMR (600 MHz, DMSO-d6) d 8.32-8.39 (m,1H), 7.55 (dt, cyanophenyl)-N- J = 1.09, 1.91 Hz, 1.H), 6.77-6.82 (m,1H), 6.72-6.77 (m, 1H), ((1R,2R,4S)-7-cyano-7- 4.06-4.16 (m, 3H),3.64-3.77 (m, 2H), 3.52-3.64 (m, 3H), 3.06- azabicyclo[2.2.1]heptan-3.16 (m, 1H), 2.14-2.28 (m, 2H), 1.99-2.13 (m, 1H), 1.77-1.90 2-yl)-3-(m, 2H), 1.53-1.73 (m, 1H), 1.20-1.33 (m, 1H) pyrrolidinecarboxamide29-1 (3S)-N-((1R,2R,4S)-7- 405 1H NMR (600 MHz, DMSO-d6) Shift 8.53 (brd, J = 4.58 Hz, cyano-7- 1H), 8.30-8.40 (m, 1H), 7.84-7.95 (m, 1H),7.35-7.43 (m, 1H), azabicyclo[2.2.1]heptan- 7.21-7.35 (m, 1H), 7.07 (s,1H), 4.25-4.48 (m, 1H), 4.08-4.19 2-yl)-1-(6-cyano-4- (m, 3H), 3.44-3.74(m, 4H), 3.06-3.19 (m, 1H), 2.04-2.30 (m, (trifluoromethyl)-2- 3H),1.78-1.88 (m, 2H), 1.53-1.72 (m, 2H), 1.24-1.32 (m, 1H) pyridinyl)-3-pyrrolidinecarboxamide 29-2 (3S)-N-((1R,2R,4S)-7- 351 1H NMR (600 MHz,DMSO-d6) Shift 8.28-8.33 (m, 1H), 6.72- cyano-7- 6.76 (m, 1H), 6.67-6.69(m, 1H), 4.08-4.14 (m, 3H), 3.61-3.66 azabicyclo[2.2.1]heptan- (m, 2H),3.49-3.54 (m, 2H), 3.06-3.11 (m, 1H), 2.34 (s, 3H) 2-yl)-1-(6-cyano-4-2.14-2.22 (m, 1H), 2.04-2.10 (m, 1H), 1.78-1.88 (m, 2H), 1.57-methyl-2-pyridinyl)-3- 1.69 (m, 2H), 1.23-1.30 (m, 2H)pyrrolidinecarboxamide 29-3 (3S)-N-((1R,2R,4S)-7- 394 1H NMR (500 MHz,CHLOROFORM-d) d 6.78-6.83 (m, 1H), cyano-7- 6.37-6.43 (m, 1H), 5.85-5.92(m, 1H), 4.28-4.38 (m, 2H), 4.04- azabicyclo[2.2.1]heptan- 4.10 (m, 1H),3.78-3.85 (m, 1H), 3.68-3.77 (m, 2H), 3.47-3.56 2-yl)-1-(4-methyl-6- (m,1H), 3.02-3.12 (m, 1H), 2.39-2.50 (m, 1H), 2.34-2.38 (m,(trifluoromethyl)-2- 2H), 2.24-2.34 (m, 1H), 2.01-2.10 (m, 1H),1.87-1.96 (m, 1H), pyridinyl)-3- 1.55-1.63 (m, 1H), 1.03-1.12 (m, 1H)pyrrolidinecarboxamide 29-4 (3S)-N-((1R,2R,4S)-7- 405 1H NMR (500 MHz,CHLOROFORM-d) Shift 7.06 (s, 1H), cyano-7- 6.73 (s, 1H), 5.72 (br d, J =4.67 Hz, 1H), 4.31-4.39 (m, 2H), azabicyclo[2.2.1]heptan- 4.07-4.17 (m,1H), 3.69-3.87 (m, 2H), 3.48-3.59 (m, 1H), 3.06 2-yl)-1-(4-cyano-6-(quin, J = 7.46 Hz, 1H), 2.42-2.53 (m, 1H), 2.28-2.41 (m, 2H),(trifluoromethyl)-2- 2.04-2.13 (m, 1H), 1.89-1.99 (m, 1H), 1.76-1.87 (m,1H), 1.71 pyridinyl)-3- (br s, 1H), 1.60 (ddd, J = 4.28, 8.76, 12.65 Hz,1H), 1.07 (dd, pyrrolidinecarboxamide J = 4.28, 12.85 Hz, 1H) 29-5(3S)-N-((1R,2R,4S)-7- 405 N/A cyano-7- azabicyclo[2.2.1]heptan-2-yl)-1-(3-cyano-6- (trifluoromethyl)-2- pyridinyl)-3-pyrrolidinecarboxamide 29-6 (3S)-N-((1R,2R,4S)-7- 381 1H NMR (600 MHz,DM50-d6) Shift 8.36 (br d, J = 5.81 Hz, cyano-7- 1H), 8.29 (s, 1H), 8.18(s, 1H), 4.06-4.17 (m, 3H), 3.72 (dd, azabicyclo[2.2.1]heptan- J = 7.90,10.72 Hz, 1H), 3.47-3.65 (m, 3H), 3.10-3.20 (m, 2H), 2-yl)-1-(6-2.14-2.28 (m, 2H), 2.06-2.14 (m, 1H), 1.78-1.89 (m, 2H), 1.57-(trifluoromethyl)-2- 1.71 (m, 2H, 1.28 (dd, J = 4.41, 12.76 Hz, 1H)pyrazinyl)-3- pyrrolidinecarboxamide 29-7 (3S)-1-(3-chloro-6- 414 1H NMR(500 MHz, CHLOROFORM-d) Shift 7.59-7.63 (m, (trifluoromethyl)-2- J =7.79 Hz, 1H), 6.90-6.99 (m, 7.78 Hz, 1H), 5.95 (br d, pyridinyl)-3- J =4.80 Hz, 1H), 4.31-4.37 (m, 2H), 4.07 (t, J = 5.00 Hz, 1H),((1R,2R,4S)-7-cyano-7- 3.88-4.01 (m, 2H), 3.78-3.85 (m, 1H), 2.97 (quin,J = 7.36 Hz, azabicyclo[2.2.1]heptan- 1H), 2.43-2.50 (m, 1H), 2.19-2.29(m, 2H), 2.02-2.14 (m, 1H), 2-yl)-3- 1.80-1.97 (m, 2H), 1.52-1.67 (m,1H), 1.24-1.33 (m, 2H), 1.01- pyrrolidinecarboxamide 1.09 (m, 1H) 30-1(3S)-N-((1R,2R,4S)-7- 325.1 1H NMR (500 MHz, CHLOROFORM-d) Shift7.12-7.20 (m, cyano-7- 1H), 6.61 (br d, J = 7.40 Hz, 1H), 6.42-6.51 (m,2H), 6.01 (br s, azabicyclo[2.2.1]heptan- 1H), 4.30-4.37 (m, 2H), 4.04(t, J = 4.93 Hz, 1H), 3.43-3.57 (m, 2-yl)-1-(3- 2H), 3.30-3.38 (m, 1H),3.01-3.08 (m, 1H), 2.38-2.48 (m, 1H), methylphenyl)-3- 2.33 (s, 3H),2.25-2.31 (m, 2H), 1.99-2.06 (m, 1H), 1.85-1.93 pyrrolidinecarboxamide(m, 1H), 1.68-1.85 (m, 2H), 1.48-1.56 (m, 1H), 1.28-1.36 (m, 1H), 1.01(dd, J = 4.02, 12.98 Hz, 1H) 30-2 (3S)-N-((1R,2R,4S)-7- 341 1H NMR (500MHz, CHLOROFORM-d) Shift 7.18 (t, J = 8.11 cyano-7- Hz, 1H), 6.36 (dd, J= 1.88, 8.11 Hz, 1H), 6.29 (br d, J = 7.53 Hz, azabicyclo[2.2.1]heptan-1H), 6.17-6.25 (m, 1H), 5.89 (br s, 1H), 4.31-4.37 (m, 2H), 4.052-yl)-1-(3- (t, J = 5.00 Hz, 1H), 3.82 (s, 3H), 3.47-3.57 (m, 2H),3.33-3.39 methoxyphenyl)-3- (m, 1H), 3.06 (quin, J = 7.14 Hz, 1H),2.38-2.50 (m, 1H), 2.25- pyrrolidinecarboxamide 2.35 (m, 2H), 1.97-2.12(m, 1H), 1.84-1.95 (m, 1H), 1.70-1.83 (m, 1H), 1.52 (ddd, J = 4.35,8.79, 12.68 Hz, 2H), 1.00 (dd, J = 3.89, 12.98 Hz, 1H) 30-37-chloro-N-((1R,2R,4S)- 344 1H NMR (500 MHz, CHLOROFORM-d) Shift 7.27(d, J = 2.59 7-cyano-7- Hz, 1H), 7.19 (dd, J = 2.60, 8.56 Hz, 1H),6.91-6.98 (m, 2H), 6.06 azabicyclo[2.2.1]heptan- (br d, J = 4.80 Hz,1H), 4.36-4.43 (m, 2H), 4.23-4.31 (m, 2H), 2-yl)-2,3-dihydro-1- 4.09 (t,J = 5.00 Hz, 1H), 2.96 (t, J = 4.41 Hz, 2H), 2.46-2.54 (m,benzoxepine-4- 1H), 2.01-2.13 (m, 1H), 1.86-1.97 (m, 2H), 1.55-1.72 (m,2H), carboxamide 1.16 (dd. J = 4.22, 12.78 Hz, 1H) 30-4(3S)-N-((1R,2R,4S)-7- 379 1H NMR (400 MHz, CHLOROFORM-d) d 7.29-7.33 (m,1H), cyano-7- 6.96-7.07 (m, 2H4), 6.73-6.84 (m, 1H), 4.28-4.36 (m, 2H),4.02- azabicyclo[2.2.1]heptan- 4.07 (m, 1H), 3.64-3.77 (m, 1H),3.54-3.60 (m, 1H), 3.25-3.33 2yl)-1-(2,5- (m, 1H), 3.03-3.13 (m, 2H),2.32-2.52 (m, 2H), 2.13-2.24 (m, dichlorophenyl)-3- 1H,), 1.96-2.06 (m,1H), 1.81-1.92 (m, 1H), 1.75-1.81 (m, 1H), pyrrolidinecarboxamide1.49-1.58 (m, 2H), 1.06-1.12 (m, 1H) 30-5 (3S)-N-((1R,2R,4S)-7- 462.9 1HNMR (600 MHz, DMSO-d6) Shift 8.32 (br d, J = 5.99 Hz, cyano-7- 1H), 6.69(s, 2H), 4.06-4.17 (m, 3H), 3.42-3.51 (m, 1H), 3.32-azabicyclo[2.2.1]heptan- 3.40 (m, 2H), 3.26-3.30 (m, 1H), 3.07-3.15 (m,1H), 2.14-2.24 2-yl)-1-(3,5-dichloro-4- (m, 2H), 2.07 (qd, J = 7.90,12.27 Hz, 1H), 1.78-1.88 (m, 2H), (trifluoromethoxy)phenyl)- 1.56-1.71(m, 2H), 1.27 (dd, J = 4.50, 12.67 Hz, 1H) 3-pyrrolidinecarboxamide 30-6(3S)-1-(3-chloro-5- 413 1H NMR (600 MHz, DMSO-d6) Shift 8.32 (br d, J =5.99 Hz, (trifluoromethyl)phenyl)- 1H), 6.90 (s, 1H), 6.80 (s, 1H), 6.70(s, 1H), 4.06-4.16 (m, 3H), N-((1R,2R,4S)-7-cyano- 3.50 (t, J = 8.76 Hz,1H), 3.31-3.42 (m, 3H), 3.08-3.15 (m, 1H), 7- 2.14-2.26 (m, 2H),2.03-2.14 (m, 1H), 1.78-1.89 (m, 2H), 1.57- azabicyclo[2.2.1]heptan-1.71 (m, 2H), 1.28 (dd, J = 4.36, 12.72 Hz, 1H) 2-yl)-3-pyrrolidinecarboxamide 30-7 (3S)-1-(3-chloro-5- 359 1H NMR (600 MHz,DMSO-d6) Shift 8.28 (br d, J = 5.99 Hz, methylphenyl)-N- 1H), 6.45 (s,1H), 6.33 (s, 1H), 6.30 (br s, 1H), 4.07-4.16 (m, (1R,2R,4S)-7-cyano-7-3H), 3.39-3.40 (m, 1H), 3.42 (t, J = 8.63 Hz, 1H), 3.17-3.28 (m,azabicyclo[2.2.1]heptan- 2H), 3.09 (quin, J = 7.67 Hz, 1H), 2.16-2.25(m, 5H), 2.06 (qd, 2-yl)-3- J = 7.92, 12.20 Hz, 1H), 1.78-1.88 (m, 2H),1.57-1.72 (m, 2H), pyrrolidinecarboxamide 1.27 (dd, J = 4.59, 12.67 Hz,1H) 30-8 (3S)-1-(5-chloro-2- 359 1H NMR (600 MHz, DMSO-d6) Shift 8.23(br d, J = 6.09 Hz, methylphenyl)-N- 1H), 7.08 (d, J = 7.99 Hz, 1H),6.81 (d, J = 8.19 Hz, 1H), 6.79 (s, (1R,2R,4S)-7-cyano-7- 1H), 4.07-4.17(m, 3H), 3.32-3.37 (m, 1H), 3.25-3.30 (m, 2H), azabicyclo[2.2.1]heptan-3.11-3.22 (m, 1H), 3.03 (quin, J = 7.72 Hz, 1H), 2.10-2.25 (m, 2-yl)-3-5H), 2.01 (qd, J = 7.55, 12.13 Hz, 1H), 1.76-1.90 (m, 2H), 1.56-pyrrolidinecarboxamide 1.72 (m, 2H), 1.26 (dd, J = 4.59, 12.67 Hz, 1H)30-9 6-(3-chlorophenyl)-N- 353 1H NMR (400 MHz, CHLOROFORM-d) Shift 8.18(dd, J = 0.98, ((1R,2R,4S)-7-cyano-7- 7.62 Hz, 2H), 7.94-8.01 (m, 2H),7.82-7.91 (m, 2H), 7.44-7.50 azabicyclo[2.2.1]heptan- (m, 2H), 4.46-4.59(m, 2H), 4.15 (t, J = 4.98 Hz, 1H), 2.59 (dddd, 2-yl)-2- J = 3.01, 5.18,11.03, 13.02 Hz, 1H), 2.05-2.17 (m, 1H), 1.92-2.04 pyridinecarboxamide(m, 2H), 1.65-1.78 (m, 1H), 1.31 (dd, J = 4.41, 12.91 Hz, 1H) 30-10N-((1R,2R,4S)-7-cyano- 387 1H NMR (600 MHz, DMSO-d6) Shift 9.16 (br d, J= 6.54 Hz, 7- 1H), 8.78-8.82 (m, 1H), 8.07-8.10 (m, 1H), 7.74-7.80 (m,1H), azabicyclo[2.2.1]heptan- 7.65-7.71 (m, 2H), 7.60 (br dd, J = 2.59,8.58 Hz, 1H), 4.32-4.39 2-yl)-4-(2,5- (m, 1H), 4.24-4.29 (m, 1H),4.16-4.21 (m, 1H), 2.17-2.26 (m, dichlorophenyl)-2- 1H), 1.61-1.93 (m,5H) pyridinecarboxamide 30-11 N-((1R,2R,4S)-7-cyano- 387 1H NMR (600MHz, DMSO-d6) Shift 9.14 (d, J = 6.36 Hz, 1H), 7- 8.77 (d, J = 5.09 Hz,1H), 8.30 (d, J = 1.27 Hz, 1H), 8.03 (dd, azabicyclo[2.2.1]heptan- J =1.91, 5.18 Hz, 1H), 7.96 (d, J = 1.82 Hz, 2H), 7.77 (t, J = 1.822-yl)-4-(3,5- Hz, 1H), 4.24-4.40 (m, 2H), 4.18 (t, J = 4.54 Hz, 1H),3.83 (d, dichlorophenyl)-2- J = 5.72 Hz, 1H), 2.39 (br s, 1H), 2.17-2.24(m, 1H), 1.75-1.89 pyridinecarboxamide (m, 2H), 1.57-1.75 (m, 1H) 30-124-(3-chlorophenyl)-N- 353 1H NMR (600 MHz, DMSO-d6) Shift 9.13 (br d, J= 6.45 Hz, ((1R,2R,4S)-7-cyano-7- 1H), 8.76 (d, J = 5.09 Hz, 1H), 8.29(s, 1H), 8.00 (dd, J = 1.32, azabicyclo[2.2.1]heptan- 5.04 Hz, 1H), 7.95(s, 1H), 7.81-7.88 (m, 1H), 7.59 (d, J = 5.00 2-yl)-2- Hz, 2H), 4.36 (brdd, J = 4.86, 11.31 Hz, 1H), 4.27 (t, J = 4.67 Hz, pyridinecarboxamide1H), 4.18 (t, J = 4.68 Hz, 1H), 2.17-2.24 (m, 1H), 1.75-1.92 (m, 4H),1.69 (br d, J = 10.45 Hz, 1H) 30-13 (3S)-N-(1R,2R,4S)-7- 409 1H NMR (400MHz, CHLOROFORM-d) Shift 6.46 (s, 2H), cyano-7- 5.79 (br d, J = 4.98 Hz,1H), 4.29-4.38 (m, 2H), 4.07 (t, J = 5.03 azabicyclo[2.2.1]heptan- Hz,1H), 3.83 (s, 3H), 3.36-3.47 (m, 3H), 3.22-3.36 (m, 1H),2-yl)-1-(3,5-dichloro-4- 3.00 (quin, J = 7.57 Hz, 1H), 2.42-2.52 (m,1H), 2.21-2.34 (m, methoxyphenyl)-3- 2H), 2.01-2.11 (m, 2H), 1.72-1.97(m, 2H), 1.52-1.58 (m, 1H) pyrrolidinecarboxamide 30-14(3S)-N-(1R,2R,4S)-7- 397 1H NMR (400 MHz, CHLOROFORM-d) Shift 6.43 (d, J= 5.29 cyano-7- Hz, 2H), 5.83 (br d, J = 5.29 Hz, 1H), 4.29-4.37 (m,2H), 4.07 (t, azabicyclo[2.2.1]heptan- J = 4.98 Hz, 1H), 3.67-3.72 (m,1H), 3.38-3.50 (m, 2H), 3.22-3.33 2-yl)-1-(3,5-dichloro-4- (m, 2H), 3.04(quin, J = 7.62 Hz, 1H), 2.42-2.51 (m, 1H), 2.22- fluorophenyl)-3- 2.35(m, 2H), 2.00-2.11 (m, 1H), 1.77-1.97 (m, 1H), 1.52-1.61pyrrolidinecarboxamide (m, 2H), 1.05 (dd, J = 4.25, 12.85 Hz, 1H) 30-15(3S)-N-((1R,2R,4S)-7- 351 1H NMR (600 MHz, DMSO-d6) Shift 8.28 (br d, J= 6.18 Hz, cyano-7- 1H), 7.02 (t, J = 7.81 Hz, 1H), 6.31 (br d, J = 8.08Hz, 2H), 6.24 (s, azabicyclo[2.2.1]heptan- 1H), 4.07-4.17 (m, 3H),3.38-3.52 (m, 2H), 3.21-3.29 (m, 3H), 2-yl)-1-(3- 3.08 (quin, J = 7.77Hz, 1H), 2.14-2.21 (m, 2H), 2.07 (qd, J = 8.11, cyclopropylphenyl)-3-12.09 Hz, 1H), 1.77-1.90 (m, 3H), 1.57-1.71 (m, 2H), 1.24-1.31pyrrolidinecarboxamide (m, 1H), 0.84-0.94 (m, 2H), 0.59-0.67 (m, 2H)30-16 N-((1R,2R,4S)-7-cyano- 394.8 1H NMR (600 MHz, DMSO-d6) Shift 8.25(br t, J = 5.72 Hz, 7- 1H), 6.97 (dd, J = 1.73, 3.09 Hz, 2H), 6.93 (s,1H), 4.08-4.16 (m, azabicyclo[2.2.1]heptan- 4H), 4.01 (br d, J = 11.54Hz, 1H), 3.67-3.76 (m, 2H), 3.58 (br d, 2-yl)-4-(3,5- J = 12.26 Hz, 1H),2.81-2.94 (m, 2H), 2.12 (br s, 1H), 1.74-1.84 dichlorophenyl)-2- (m,2H), 1.61-1.74 (m, 2H), 1.54 (td, J = 4.48, 12.56 Hz, 1H)morpholinecarboxamide 30- (3S)-N-((1R,2R,4S)-7- 413 1H NMR (500 MHz,CHLOROFORM-d) d 7.18-7.19 (m, 1H), 17 cyano-7- 6.92-6.93 (m, 1H),6.45-6.51 (m, 1H), 4.30-4.35 (m, 2H), 4.05- azabicyclo[2.2.1]heptan-4.08 (m, 1H), 3.64-3.70 (m, 1H), 3.56-3.60 (m, 1H), 3.33-3.382-yl)-1-(2,3,5- (m, 1H), 3.14-3.20 (m, 1H), 3.02-3.08 (m, 1H), 2.43-2.51(m, trichlorophenyl)-3- 1H), 2.31-2.39 (m, 1H), 2.16-2.24 (m, 1H),2.00-2.08 (m, 2H), pyrrolidinecarboxamide 1.85-1.93 (m, 1H), 1.74-1.80(m, 1H), 1.51-1.55 (m, 1H), 1.05- 1.09 (m, 1H) 31-1N-((1R,2R,4S)-7-cyano- 376 1H NMR (600 MHz, DMSO-d6) Shift 9.09 (s, 1H),8.34 (d, 7- J = 5.99 Hz, 1H), 8.24 (s, 1H), 7.99 (d, J = 1.79 Hz, 2H),7.62 (s, azabicyclo[2.2.1]heptan- 1H), 4.20-4.30 (m, 2H), 4.17 (t, J =4.87 Hz, 1H), 2.20-2.27 (m, 2-yl)-1-(3,5- 1H), 1.80-1.93 (m, 2H),1.62-1.72 (m, 2H), 1,44 ( dd, J = 4.67, dichlorophenyl)-1H- 12.77 Hz,1H) pyrazole-4-carboxamide 31-2 3-chloro-N-((1R,2R,4S)- 410 1H NMR (600MHz, DMSO-d6) Shift 9.13 (s, 1H), 8.37 (br d, 7-cyano-7- J = 5.68 Hz,1H), 7.93 (d, J = 1.79 Hz, 2H), 7.68 (t, J = 1.75 Hz,azabicyclo[2.2.1]heptan- 1H), 4.21-4.29 (m, 2H), 4.18 (t, J = 4.94 Hz,1H), 2.19-2.28 (m, 2-yl)-1-(3,5- 1H), 1.96 (ddd, J = 4.40, 8.87, 12.88Hz, 1H), 1.81-1.90 (m, 1H), dichlorophenyl)-1H- 1.61-1.75 (m, 2H), 1.39(dd, J = 4.24, 12.65 Hz, 1H) pyrazole-4-carboxamide 32-1(3S)-1-(3-chloro-5- 370 1H NMR (600 MHz, DMSO-d6) Shift 8.32 (br d, J =6.18 Hz, cyanophenyl)-N- 1H), 7.06 (s, 1H), 6.90 (s, 1H), 6.84 (t, J =1.95 Hz, 1H), 4.07- ((1R,2R,4S)-7-cyano-7- 4.17 (m, 3H), 3.43-3.52 (m,1H), 3.21-3.41 (m, 3H), 3.12 (quin, azabicyclo[2.2.1]heptan- J = 7.52Hz, 1H), 2.15-2.24 (m, 2H), 2.07 (qd, J = 7.87, 12.6 Hz, 2-yl)-3- 1H),1.78-1.88 (m, 2H), 1.56-1.71 (m, 2H), 1.27 (dd, J = 4.50,pyrrolidinecarboxamide 12.76 Hz, 1H) 32-2 (3S)-1-(2-chloro-5- 370 1H NMR(600 MHz, DMSO-66) Shift 8.24-8.33 (m, 1H), 7.50 cyanophenyl)-N- (d, J =8.08 Hz, 1H), 7.30 (d, J = 1.73 Hz, 1H), 7.22 (dd, J = 1.86,((1R,2R,4S)-7-cyano-7- 8.13 Hz, 1H), 4.06-4.17 (m, 3H), 3.46-3.61 (m,3H), 3.32-3.41 azabicyclo[2.2.1]heptan- (m, 1H), 3.04 (quin, J = 7.72Hz, 1H), 2.10-2.22 (m, 2H), 2.02 2-yl)-3- (qd, J = 7.79, 12.05 Hz, 1H),1.76-1.90 (m, 2H), 1.55-1.71 (m, prrolidinecarboxamide 2H), 1.26 (dd, J= 4.54, 12.72 Hz, 1H) 32-3 (3S)-N-((1R,2R,4S)-7- 438 1H NMR (600 MHz,DMSO-d6) Shift 8.25 (br d, J = 5.99 Hz, cyano-7- 1H), 7.52 (s, 1H), 6.23(d, J = 2.00 Hz, 1H), 5.06 (td, J = 6.83, azabicyclo[2.2.1]heptan- 13.58Hz, 1H), 4.06-4.16 (m, 3H), 3.70 (dd, J = 8.13, 10.40 Hz,2-yl)-1-(2-oxo-1-(2- 1H), 3.41-3.54 (m, 3H), 2.91-3.05 (m, 1H),2.13-2.28 (m, 1H), propanyl)-5- 2.04-2.13 (m, 1H), 1.92-2.04 (m, 1H),1.75-1.90 (m, 2H), 1.55- (trifluoromethyl)-1,2- 1.71 (m, 2H), 1.24-1.36(m, 7H) dihydro-3-pyridinyl)-3- pyrrolidinecarboxamide 32-4(3S)-N-((1R,2R,4S)-7- 378.8 1H NMR (600 MHz, DMSO-d6) Shift 8.31 (br d,J = 5.99 Hz, cyano-7- 1H), 7.33 (d, J = 8.90 Hz, 1H), 6.69 (d, J = 2.82Hz, 1H), 6.52 (dd, azabicyclo[2.2.1]heptan- J = 2.82, 8.90 Hz, 1H),4.07-4.17 (m, 3H), 3.38-3.52 (m, 2H), 2-yl)-1-(3,4- 3.22-3.28 (m, 2H4),3.07-3.15 (m, 1H), 2.14-2.23 (m, 2H), 2.07 dichlorophenyl)-3- (qd, J =7.96, 12.36 Hz, 1H), 1.77-1.88 (m, 2H), 1.55-1.72 (m,pyrrolidinecarboxamide 2H), 1.23-1.31 (m, 1H), 1.16 (t, J = 7.27 Hz, 1H)32-5 (3S)-N-((1R,2R,4S)-7- 378.8 1H NMR (600 MHz, DMSO-d6) Shift 8.27(br d, J = 5.90 Hz, cyano-7- 1H), 7.20 (t, J = 8.08 Hz, 1H), 7.09 (dd, J= 1.32, 7.95 Hz, 1H), azabicyclo[2.2.1]heptan- 6.96 (dd, J = 1.18, 8.36Hz, 1H), 4.06-4.18 (m, 3H), 3.19-3.35 (m, 2-yl)-1-(2,3- 3H), 3.04 (quin,J = 7.74 Hz, 1H), 2.90-2.97 (m, 1H), 2.09-2.21 dichlorophenyl)-3- (m,2H), 2.02 (qd, J = 7.74, 12.13 Hz, 1H), 1.76-1.89 (m, 2H),pyrrolidinecarboxamide 1.56-1.72 (m, 2H), 1.26 (dd, J = 4.50, 12.76 Hz,1H), 1.17 (t, J = 7.27 Hz, 1H) 32-6 (3S)-1-(2-chloro-5- 413 1H NMR (600MHz, DMSO-d6) Shift 8.29 (br d, J = 6.18 Hz, (trifluoromethyl)phenyl)-1H), 7.53 (d, J = 8.17 Hz, 1H), 7.07-7.15 (m, 2H), 4.08-4.16 (m,N-((1R,2R,4S)-7-cyano- 3H), 3.49-3.63 (m, 3H), 3.32-3.43 (m, 1H), 3.06(quin, J = 7.65 7- Hz, 1H), 2.11-2.21 (m, 2H), 2.03 (qd, J = 7.91, 12.07Hz, 1H), azabicyclo[2.2.1]heptan- 1.78-1.88 (m, 2H), 1.56-1.72 (m, 2H),1.27 (dd, J = 4.59, 12.76 2-yl)-3- Hz, 1H) pyrrolidinecarboxamide 33-(1R,4R,5R)-N- 390.8 1H NMR (500 MHz, CHLOROFORM-d) Shift 6.77 (t, J =1.69 1-1 (1R,2R,4S)-7-cyano-7- Hz, 1H), 6.65 (d, J = 1.69 Hz, 2H), 5.96(br d, J = 4.67 Hz, 1H), azabicyclo[2.2.1]heptan- 4.32-4.39 (m, 2H),4.09 (t, J = 5.00 Hz, 1H), 3.85 (t, J = 9.86 Hz, 2-yl)-2-(3,5- 1H),3.33-3.45 (m, 2H), 3.02-3.08 (m, 1H), 2.46-2.54 (m, 1H),dichlorophenyl)-2- 2.04-2.13 (m, 1H), 1.83-1.98 (m, 2H), 1.61 (ddd, J =4.35, 8.66, azabicyclo[2.2.1]heptan- 12.55 Hz, 2H), 1.08 (dd, J = 4.15,12.85 Hz, 1H), 0.79-0.92 (m, 4-carboxamide 2H) 33- (1R,4R,5R)-N- 390.81H NMR (500 MHz, CHLOROFORM-d) Shift 6.78 (t, J = 1.75 1-2((1R,2R,4S)-7-cyano-7- Hz, 1H), 6.66 (d, J = 1.69 Hz, 2H), 5.91 (br d, J= 4.80 Hz, 1H), azabicyclo[2.2.1]heptan- 4.32-4.39 (m, 2H), 4.10 (t, J =4.93 Hz, 1H), 3.87 (t, J = 9.93 Hz, 2-yl)-2-(3,5- 1H), 3.45 (dt, J =5.71, 9.21 Hz, 1H), 3.37 (ddd, J = 2.72, 5.45, dichlorophenyl)-2- 6.49Hz, 1H), 3.05 (dd, J = 8.95, 10.12 Hz, 1H), 2.47-2.54 (m,azabicyclo[3.1.0]hexane- 1H), 2.08 (dtd, J = 3.96, 8.09, 12.31 Hz, 1H),1.80-1.97 (m, 2H), 4-carboxamide 1.54-1.65 (m, 1H), 1.54-1.64 (m, 1H),1.09 (dd, J = 4.22, 12.91 Hz, 1H), 0.91 (td, J = 5.69, 8.21 Hz, 1H),0.79 (dt, J = 2.66, 5.42 Hz, 1H) 1- (3R)-6-chloro-N- 369.1 1H NMR(DMSO-d6) δ: 10.82 (s, 1H), 8.13 (br d, J = 6.0 Hz, 67-1((1R,2R,4S)-7-cyano-7- 1H), 7.31 (d, J = 1.7 Hz, 1H), 7.16 (d, J = 8.5Hz, 1H), 6.89 (dd, azabicyclo[2.2.1]heptan- J = 8.5, 2.0 Hz, 1H),4.00-4.10 (m, 3H), 2.62-2.76 (m, 3H), 2.47- 2-yl)-2,3,4,9-tetrahydro-2.59 (m, 2H), 2.03-2.17 (m, 1H), 1.89-2.00 (m, 1H), 1.77-1.841H-carbazole-3- (m, 1H) 1.69-1.77 (m, 2H), 1.55-1.64 (m, 1H), 1.48-1.55(m, carboxamide 1H), 1.20 (dd, J = 12.7, 4.4 Hz, 1H) 12-(1S,3S)-N-((1R,2R,4S)- 378.0 1H NMR (DMSO-d6) δ: 8.13 (br d, J = 6.0 Hz,1H), 7.52 (d, 2-1 7-cyano-7- J = 2.5 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H),7.30 (dd, J = 8.5, 2.5 Hz, azabicyclo[2.2.1]heptan- 1H), 4.06-4.15 (m,3H), 3.34-3.45 (m, 1H), 2.79-2.86 (m, 1H), 2-yl)-3-(2,5- 2.12-2.24 (m,2H), 1.98-2.06 (m, 1H), 1.85-1.94 (m, 2H), 1.71-dichlorophenyl)cyclopen- 1.85 (m, 3H), 1.62-1.71 (m, 2H), 1.56-1.62 (m,1H), 1.25 (dd., tanecarboxamide J = 12.7, 4.5 Hz, 1H) 12-(1R,3R)-N-((1R,2R,4S)- 378.0 1H NMR (DMSO-d6) δ: 8.10 (br d, J = 6.0 Hz,1H), 7.45 (d, 2-2 7-cyano-7- J = 8.5 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H),7.30 (dd, J = 8.5, 2.6 Hz, azabicyclo[2.2.1]heptan- 1H), 4.06-4.14 (m,3H), 3.45-3.59 (m, 1H), 2.86-2.93 (m, 1H), 2-yl)-3-(2,5- 2.12-2.20 (m,2H), 2.00-2.11 (m, 2H), 1.71-1.85 (m, 4H), 1.61-dichlorophenyl)cyclopen- 1.71 (m, 2H), 1.53-1.61 (m, 1H), 1.24 (dd, J =12.7, 4.5 Hz, 1H) tanecarboxamide 12- (1S,3R)-N-((1R,2R,4S)- 378.0 1HNMR (DMSO-d6) δ: 8.12 (br d, J = 5.7 Hz, 1H), 7.52 (d, 2-3 7-cyano-7- J= 2.5 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.30 (dd, J = 8.5, 2.5 Hz,azabicyclo[2.2.1]heptan- 1H), 4.06-4.14 (m, 3H), 2.79-2.86 (m, 1H),2.12-2.28 (m, 2H), 2-yl)-3-(2,5- 1.97-2.05 (m, 1H), 1.83-1.97 (m, 2H),1.75-1.83 (m, 2H), 1.53- dichlorophenyl)cyclopen- 1.75 (m, 4H), 1.25(dd, J = 12.6, 4.1 Hz, 1H) tanecarboxamide 15- (5R)-N-((1R,2R,4S)-7-427.2 1H NMR (DMSO-d6) δ: 8.17 (br d, J = 5.9 Hz, 1H), 8.11 (t, J = 7.915-2 cyano-7- Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.62 (s, 1H), 7.58 (d,J = 7.5 Hz, azabicyclo[2.2.1]heptan- 1H), 4.09-4.16 (m, 3H), 3.35 (br s,2H), 3.01-3.10 (m, 1H), 2.65- 2-yl)-1-(6-(1,1- 2.77 (m, 1H), 2.55-2.63(m, 2H), 2.13-2.22 (m, 1H), 2.07-2.11 difluoroethyl)-2- (m, 1H),1.97-2.07 (m, 1H), 1.72-1.88 (m, 3H), 1.63-1.69 (m, pyridinyl)-4,5,6,7-1H), 1.51-1.63 (m, 1H), 1.19-1.34 (m, 2H) tetrahydro-1H-indazole-5-carboxamide 15- (5R)-N-((1R,2R,4S)-7- 429.0 1H NMR (DMSO-d6) δ: 8.18(br d, J = 5.9 Hz, 1H), 8.04 (t, J = 8.0 16-2 cyano-7- Hz, 1H),7.66-7.72 (m, 1H), 7.61 (s, 1H), 6.95 (d, J = 8.0 Hz, 1H),azabicyclo[2.2.1]heptan- 4.08-4.16 (m, 3H), 3.34 (br s, 1H), 2.99-3.08(m, 1H), 2.70 (br 2-yl)-1-(6- dd, J = 14.8, 4.6 Hz, 1H), 2.55-2.62 (m,2H), 2.14-2.22 (m, 1H), (difluoromethoxy)-2- 2.03-2.11 (m, 1H),1.70-1.88 (m, 3H), 1.57-1.69 (m, 2H), 1.22- pyridinyl)-4,5,6,7- 1.32 (m,2H) tetrahydro-1H-indazole- 5-carboxamide 15- (5S)-N-((1R,2R,4S)-7-428.0 1H NMR (DMSO-d6) δ: 8.30 (s, 1H), 8.22 (br d, J = 6.2 Hz, 1H),16-3 cyano-7- 7.92-7.98 (m, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.40-7.44 (m,1H), azabicyclo[2.2.1]heptan- 4.07-4.17 (m, 3H), 2.77-2.82 (m, 1H),2.61-2.76 (m, 3H), 2.52- 2-yl)-2-(6-(1- 2.58 (m, 1H), 2.14-2.22 (m, 1H),2.04 (br d, J = 9.5 Hz, 1H), 1.71- cyanocyclopropyl)-2- 1.87 (m, 7H),1.64-1.69 (m, 1H), 1.55-1.64 (m, 1H), 1.22-1.31 pyridinyl)-4,5,6,7- (m,1H) tetrahydro-2H-indazole- 5-carboxamide 15- (5S)-N-((1R,2R,4S)-7-427.2 1H NMR (DMSO-d6) δ: 8.38 (s, 1H), 8.23 (d, J = 6.0 Hz, 1H), 15-3cyano-7- 8.09 (t, J = 7.9 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.55 (d, J= 7.6 Hz, azabicyclo[2.2.1]heptan- 1H), 4.07-4.17 (m, 3H), 2.73-2.89 (m,2H), 2.62-2.71 (m, 2H), 2-yl)-2-(6-(1,1- 2.52-2.60 (m, 2H), 2.14-2.22(m,1H), 2.04-2.09 (m, 3H), 1.73- difluoroethyl)-2- 1.89 (m, 3H),1.63-1.70 (m, 1H), 1.57-1.63 (m, 1H), 1.28 (dd, pyridinyl)-4,5,6,7- J =12.8, 4.5 Hz, 1H) tetrahydro-2H-indazole- 5-carboxamide 15-(5S)-N-((1R,2R,4S)-7- 429.0 1H NMR (DMSO-d6) δ: 8.41 (s, 1H), 8.21 (brd, J = 6.1 Hz, 1H) 16-3 cyano-7- 8.01 (t, J = 8.0 Hz, 1H), 7.94 (s, 1H),7.60 (d, J = 8.0 Hz, 1H), 6.91 azabicyclo[2.2.1]heptan- (d, J = 8.0 Hz,1H), 4.09-4.15 (m, 3H), 2.75-2.92 (m, 2H), 2.59- 2-yl)-2-(6- 2.70 (m,2H), 2.55 (tdd, J = 11.2, 5.2, 2.4 Hz, 1H), 2.14-2.22 (m,(difluoromethoxy)-2- 1H), 2.00-2.10 (m, 1H), 1.72-1.89(m, 3H), 1.57-1.70(m, 2H), pyridinyl)-4,5,6,7- 1.22-1.32 (m, 1H) tetrahydro-2H-indazole-5-carboxamide 15- (5R)-N-((1R,2R,4S)-7- 427.2 1H NMR (DMSO-d6) δ: 8.39(s, 1H), 8.21 (br d, J = 6.0 Hz, 1H), 15-4 cyano-7- 8.09 (t, J = 8.0 Hz,1H), 7.93 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 7.5 Hz,azabicyclo[2.2.1]heptan- 1H), 4.09-4.16 (m, 3H), 2.74-2.91 (m, 2H),2.52-2.68 (m, 4H), 2-yl)-2-(6-(1,1- 2.14-2.22 (m, 1H), 2.02-2.07 (m,3H), 1.73-1.88 (m, 3H), 1.52- difluoroethyl)-2- 1.70 (m, 2H), 1.27 (dd,J = 12.6, 4.3 Hz, 1H) pyridinyl)-4,5,6,7- tetrahydro-2H-indazole-5-carboxamide 15- (5R)-N-(1R,2R,4S)-7- 429.0 1H NMR (DMSO-d6) δ: 8.40(s, 1H), 8.23 (d, J = 6.1 Hz, 1H), 16-4 cyano-7- 8.01 (t, J = 8.0 Hz,1H), 7.94 (t, J = 74.0 Hz, 1H), 7.60 (d, J = 8.0azabicyclo[2.2.1]heptan- Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 4.07-4.17(m, 3H), 2.73-2.83 2-yl)-2-(6- (m, 2H), 2.62-2.71 (m, 2H), 2.53-2.60 (m,1H), 2.14-2.21 (m, (difluoromethoxy)-2- 1H), 2.01-2.09 (m, 1H),1.73-1.88 (m, 3H), 1.57-1.70 (m, 2H), pyridinyl)-4,5,6,7- 1.22-1.31 (m,1H) tetrahydro-2H-indazole- 5-carboxamide 15- (5R)-N-((1R,2R,4S)-7-413.0 1H NMR (DMSO -do) δ: 8.32 (s, 1H), 8.23 (d, J = 6.3 Hz, 1H), 17-4cyano-7- 8.11 (t, J = 8.0 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.55 (d, J= 7.4 Hz, azabicyclo[2.2.1]heptan- 1H), 6.96 (t, J = 54.8 Hz, 1H),4.08-4.15 (m, 3H), 2.73-2.86 (m, 2-yl)-2-(6- 2H), 2.62-2.71 (m, 2H),2.54-2.60 (m, 1H), 2.15-2.21 (m, 1H), (difluoromethyl)-2- 2.03-2.09 (m,1H), 1.75-1.88 (m, 3H), 1.63-1.71 (m, 1H), 1.57- pyridinyl)-4,5,6,7-1.63 (m, 1H), 1.28 (dd, J = 12.6, 4.6 Hz, 1H) tetrahydro-2H-indazole-5-carboxamide 17-1 7-chloro-N-((1R,2R,4S)- 347.0 1H NMR (DMSO-d6) δ:7.41 (d, J = 2.4 Hz, 1H), 7.22 (dd, J = 8.5, 7-cyano-7- 2.6 Hz, 1H),6.98 (d, J = 8.6 Hz, 1H), 6.56 (br d, J = 5.1 Hz, 1H),azabicyclo[2.2.1]heptan- 4.54 (d, J = 15.7 Hz, 1H), 4.46 (d, J = 15.7Hz, 1H), 4.03-4.11 (m, 2-yl)-2,3- 2H), 3.89-4.03 (m, 3H), 3.76-3.84 (m,1H), 3.61-3.69 (m, 1H), dihydrobenzo[f][1,4]oxazepine- 2.04-2.12 (m,1H), 1.69-1.78 (m, 1H), 1.52-1.61 (m, 2H), 1.45- 4(5H)-carboxamide 1.52(m, 1H), 1.36 (dd, J = 12.6, 4.7 Hz, 1H) 18-1 7-chloro-N-((1R,2R,4S)-346.0 1H NMR (DMSO-d6) δ: 7.25 (br s, 1H), 7.03 (dd, J = 8.5, 1.7 Hz,7-cyano-7- 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.40 (br d, J = 5.2 Hz, 1H),5.71 (br azabicyclo[2.2.1]heptan- s, 1H), 4.41 (d, J = 15.6 Hz, 1H),4.32 (d, J = 15.6 Hz, 1H), 4.03- 2-yl)-1,2,3,5-tetrahydro- 4.08 (m, 1H),4.01 (t, J = 4.5 Hz, 1H), 3.94 (br dd, J = 10.5, 4.8 Hz,4H-1,4-benzodiazepine- 1H), 3.61 (td, J = 6.7, 4.2 Hz, 1H), 3.39-3.48(m, 1H), 3.04-3.11 4-carboxamide (m, 1H), 2.97-3.04 (m, 1H), 2.05-2.12(m, 1H), 1.70-1.77 (m, 1H), 1.59-1.66 (m, 1H), 1.52-1.58 (m, 1H),1.46-1.52 (m, 1H), 1.37 (dd, J = 12.6, 4.6 Hz, 1H) 19-11-(6-acetamido-2- 450.0 1H NMR (DMSO-d6) δ: 10.68-10.74 (m, 1H), 9.14(s, 1H), pyridinyl)-6-chloro-N- 8.82-8.87 (m, 1H), 8.53 (s, 1H), 8.02(s, 1H), 7.93-8.00 (m, 2H), ((1R,2R,4S)-7-cyano-7- 7.67-7.71 (m, 1H),4.26-4.33 (m, 2H), 4.17 (t, J = 4.8 Hz, 1H), azabicyclo[2.2.1]heptan-2.11-2.36 (m, 4H), 2.00-2.10 (m, 1H), 1.80-1.87 (m, 1H), 1.70-2-yl)-1H-indazole-5- 1.79 (m, 1H), 1.61 (ddd, J = 12.1, 8.9, 3.6 Hz,1H), 1.41 (dd, carboxamide J = 12.7, 4.0 Hz, 1H) 21-(5R)-N-((1R,2R,4S)-7- 377.0 1H NMR (CHLOROFORM-d) δ: 7.59-7.75 (m, 2H),7.47 (br s, 1-1 cyano-7- 1H), 6.96-7.09 (m, 1H), 5.92 (br s, 1H), 4.34(br s, 2H), 4.05 (br azabicyclo[2.2.1]heptan- s, 1H), 3.36 (br d, J =13.2 Hz, 1H), 3.20 (br s, 1H), 2.73 (br s, 2-yl)-1-(6-methyl-2- 2H),2.54 (br s, 3H), 2.45 (br s, 1H), 2.26 (br s, 1H), 2.04 (br s,pyridinyl)-4,5,6,7- 2H), 1.82-1.97 (m, 2H), 1.77 (br s, 1H), 1.57 (br s,1H), 1.07 (br tetrahydro-1H-indazole- d, J = 9.7 Hz, 1H) 5-carboxamide21- (5S)-N-(1R,2R,4S)-7- 377.0 1H NMR (CHLOROFORM-d) δ: 7.63-7.70 (m,H), 7.48 (s, 1-2 cyano-7- 1H), 7.03 (br d, J = 6.9 Hz, 1H), 5.88 (br s,1H), 4.29-4.37 (m, azabicyclo[2.2.1]heptan- 2H), 4.05 (br t, J = 4.3 Hz,1H), 3.36 (br d, J = 16.9 Hz, 1H), 3.14- 2-yl)-1-(6-methyl-2- 3.22 (m,1H), 2.74-2.78 (m, 1H), 2.54 (s, 3H), 2.44 (br s, 1H),pyridinyl)-4,5,6,7- 2.29 (br s, 1H), 2.05 (br s, 2H), 1.95 (br s, 1H),1.83-1.91 (m, tetrahydro-1H-indazole- 1H), 1.76-1.83 (m, 1H), 1.51-1.62(m, 2H), 1.05 (br d, J = 10.8 5-carboxamide Hz, 1H) 21-(5R)-N-((1R,2R,4S)-7- 377.0 1H NMR (CHLOROFORM-d) δ: 8.36 (s, 1H),7.64-7.70 (m, 1-3 cyano-7- 2H), 7.00 (d, J = 6.2 Hz, 1H), 5.63 (br d, J= 4.9 Hz, 1H), 4.31-4.41 azabicyclo[2.2.1]heptan- (m, 2H), 4.06 (t, J =4.9 Hz, 1H), 2.92-3.02 (m, 1H), 2.85-2.91 2-yl)-2-(6-methyl-2- (m, 2H),2.78 (ddd, J = 16.7, 11.3, 5.7 Hz, 1H), 2.55 (s, 3H), 2.11-pyridinyl)-4,5,6,7- 2.22 (m, 1H), 1.97-2.10 (m, 2H), 1.74-1.96 (m, 3H),1.56 (tt, tetrahydro-2H-indazole- J = 8.5, 4.4 Hz, 2H), 1.02 (dd, J =12.8, 4.4 Hz, 1H) 5-carboxamide 21- (5S)-N-((1R,2R,4S)-7- 377.0 1H NMR(CHLOROFORM-d) δ: 8.34 (s, 1H), 7.64-7.68 (m, 14 cyano-7- 2H), 7.00 (dd,J = 5.5, 2.8 Hz, 1H), 5.62 (br s, 1H), 4.33-4.39 (m,azabicyclo[2.2.1]heptan- 2H), 4.06 (t, J = 4.9 Hz, 1H), 2.94-2.99 (m,1H), 2.84-2.92 (m, 2-yl)-2-(6-methyl-2- 2H), 2.77 (ddd, J = 16.7, 11.2,5.8 Hz, 1H), 2.54 (s, 3H), 2.18 (or pyridinyl)-4,5,6,7- d, J = 13.1 Hz,1H), 1.99-2.08 (m, 2H), 1.91 (br t, J = 12.7 Hz, 1H),tetrahydro-2H-indazole- 1.79 (ddd, J = 13.3, 8.9, 4.5 Hz, 1H), 1.51-1.61(m, 3H), 1.02 (dd, 5-carboxamide J = 12.8. 4.0 Hz, 1H) 21-(5S)-N-((1R,2R,4S)-7- 403.2 1H NMR (DMSO-d6) δ: 8.27 (s, 1H), 8.22 (d, J= 6.1 Hz, 1H), 2-3 cyano-7- 7.74 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 8.3Hz, 1H), 7.17 (d, J = 7.6 Hz, azabicyclo[2.2.1]heptan- 1H), 4.07-4.17(m, 3H), 2.74-2.82 (m, 2H), 2.57-2.70 (m, 2H), 2-yl)-2-(6-cyclopropyl-2.53-2.55 (m, 1H), 2.14-2.21 (m, 1H), 2.08-2.14 (m, 1H), 1.98-2-pyridinyl)-4,5,6,7- 2.06 (m, 1H), 1.78-1.88 (m, 2H), 1.74 (qd, J =12.3, 5.3 Hz, 1H), tetrahydro-2H-indazole- 1.62-1.70 (m, 1H), 1.56-1.62(m, 1H), 1.22-1.31 (m, 1H), 0.95- 5-carboxamide 1.02 (m, 4H) 21-(5R)-N-((1R,2R,4S)-7- 403.2 1H NMR (DMSO-d6) δ: 8.21-8.28 (m, 2H),7.70-7.77 (m, 1H), 2-4 cyano-7- 7.48-7.57 (m, 1H), 7.12-7.20 (m, 1H),4.07-4.18 (m, 3H), 2.70- azabicyclo[2.2.1]heptan- 2.83 (m, 2H),2.59-2.70 (m, 2H), 2.53-2.57 (m, 1H), 2.00-2.22 2-yl)-2-(6-cyclopropyl-(m, 3H), 1.56-1.89 (m, 5H), 1.22-1.31 (m, 1H), 0.94-1.04 (m,2-pyridinyl)-4,5,6,7- 4H) tetrahydro-2H-indazole- 5-carboxamide 20-N-((1R,2R,4S)-7-cyano- 394.0 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.04(d, J = 6.75 77 7- Hz, 17 H) 1.15-1.37 (m, 5H) 1.59-azabicyclo[2.2.1]heptan- 1.69 (m, 3 H) 1.87-2.00 (m, 6 H) 2.02-2.21 (m,6 H) 2.26 (s, 1 2-yl)-3-(2- H) 2.31-2.40 (m, 13 H) 2.45 (s, 1methylpropoxy)-4-(3- H) 2.49-2.57 (m, 3 H) 3.78 (s, 1 H) 3.90 (s, 3 H)3.91 (s, 3 H) methyl-1H-pyrazol-1- 4.11 (t, J = 4.93 Hz, 3 H) 4.41-4.55yl)benzamide (m, 6 H) 5.31 (s, 1 H) 6.04 (d, J = 10 Hz, 1 H) 6.09 (s, 1H) 6.17 (s, 1 H) 6.25 (d, J = 2.34 Hz, 3 H) 6.37 (br d, J = 4.67 Hz, 3H) 7.24-7.31 (m, 5 H) 7.49 (d, J = 1.95 Hz, 2 H) 7.58 (d, J = 1.82 Hz, 3H) 7.89 (d, J = 8.30 Hz, 3 H) 8.18 (d, J = 2.47 Hz, 3 H)The following examples were purified via chiral chromatography by themethod given:

Ex # Name Chiral Purification Conditions 1-68-2(3S)-6-chloro-N-((1R,2R,4S)-7-cyano-7- SFC = Chiralpak IC 2 × 25 cm, 5um azabicyclo[2.2.1]heptan-2-yl)-2,3,4,9- column (35% methanol, 80mL/min) tetrahydro-1H-carbazole-3-carboxamide 2-24-12-chloro-N-((1R,2R,4S)-7-cyano-7- SFC Method: Chiralpak AD-H (250 ×azabicyclo[2.2.1]heptan-2-yl)-4-((3R)-3- 21 mm, 5 μm); mobile phase:60:40 (A:B), cyano-3-methyl-2,3-dihydro-1H-inden-5- A = liquid CO2, B =methanol, flow yl)benzamide rate: 70 ml/min; 20 mg/injection 2-24-22-chloro-N-((1R,2R,4S)-7-cyano-7- SFC Method: Chiralpak AD-H (250 ×azabicyclo [2.2.1]heptan-2-yl)-4-((3S)-3- 21 mm, 5 μm); mobile phase:60:40 (A:B), cyano-3-methyl-2,3-dihydro-1H-inden-5- A = liquid CO2, B =methanol, flow yl)benzamide rate: 70 ml/min; 20 mg/injection 2-27-2(1S,6R,7R)-N-((1R,2R,4S)-7-cyano-7- SFC Method: ChiralPak AD-H (250 ×azabicyclo[2.2.1]heptan-2-yl)-3-(3,5- 21 mm, 5 μm); mobile phase: 70:30(A:B), dichlorophenyl)-3-azabicyclo[4.1.0]heptane-7- A = liquid CO2, B =methanol, flow carboxamide rate: 100 mL/min; 25 mg/injection 2-27-1(1R,6S,7R)-N-((1R,2R,4S)-7-cyano-7- SFC Method: ChiralPak AD-H (250 ×azabicyclo[2.2.1]heptan-2-yl)-3-(3,5- 21 mm, 5 μm); mobile phase: 70:30(A:B), dichlorophenyl)-3-azabicyclo[4.1.0]heptane-7- A = liquid CO2, B =methanol, flow carboxamide rate: 100 mL/min; 25 mg/injection 2-31-2(1S,5S)-N-((1R,2R,4S)-7-cyano-7- Chiralpak AD-H (150 × 4.6 mm, 5 μm);azabicyclo[2.2.1]heptan-2-yl)-3-(3,5- mobile phase: 70:30 (A:B), A =liquid dichlorophenyl)-3-azabicyclo[3.1.0]hexane-1- CO2, B = methanol,flow rate: 120 carboxamide ml/min; Sample load: 100 mg/4 mL, 25mg/injection 2-31-2 (1R,5R)-N-((1R,2S,4S)-7-cyano-7- Chiralpak AD-H (150× 4.6 mm, 5 μm); azabicyclo[2.2.1]heptan-2-yl)-3-(3,5- mobile phase:70:30 (A:B), A = liquid dichlorophenyl)-3-azabicyclo[3.1.0]hexane-1-CO2, B = methanol, flow rate: 120 carboxamide ml/min; Sample load: 100mg/4 mL, 25 mg/injection 2-39-1 2-chloro-N-((1R,2R,4S)-7-cyano-7- STCMethod: ChiralPak AD-H (250 × azabicyclo[2.2.1]heptan-2-yl)-4-((3S)-3-21 mm, 5 μm); mobile phase: 60:40 (A:B), cyano-1-piperidinyl)benzamide A= liquid CO2, B = methanol, flow rate: 80 ml/min; 40 mg/injection 2-39-22-chloro-N-((1R,2R,4S)-7-cyano-7- SFC Method: ChiralPak AD-H (250 ×azabicyclo[2.2.1]heptan-2-yl)-4-((3R)-3- 21 mm, 5 μm); mobile phase:60:40 (A:B), cyano-1-piperidinyl)benzamide A = liquid CO2, B = methanol,flow rate: 80 ml/min; 40 mg/injection 2-43-12-chloro-N-((1R,2R,4S)-7-cyano-7- SFC Method: ChiralPak AD-H (250 ×azabicyclo[2.2.1]heptan-2-yl)-4-((1S,2S,5R)- 21 mm), 5 μm); mobilephase: 60:40 (A:B), 2-cyano-6-azabicyclo[3.2.1]octan-6- A = liquid CO2,B = methanol, flow yl)benzamide rate: 80 ml/min; 40 mg/injection 2-46-2(2S)-N-((1R,2R,4S)-7-cyano-7- SPC Method: Chiralpak AS-H (250 × 30azabicyclo[2.2.1]heptan-2-yl)-1-(3,5- mm, 5 μm); mobile phase: 85:15(A:B), dichlorobenzyl)-2-azetidinecarboxamide A = liquid CO2, B =methanol, flow rate: 3 ml/min; Sample load: 80 mg/12 mL, 4 mL/injection2-46-3 (2R)-N-((1R,2R,4S)-7-cyano-7- SFC Method: Chiralpak AS-H (250 ×30 azabicyclo[2.2.1]heptan-2-yl)-1-(3,5- mm, 5 μm); mobile phase: 85:15(A:B), dichlorobenzyl)-2-azetidinecarboxamide A = liquid CO2, B =methanol, flow rate: 3 ml/min; Sample load: 80 mg/12 mL, 4 mL/injection2-48-1 2-chloro-N-((1R,2R,4S)-7-cyano-7- SFC Method: Chiralpak IG (250 ×30 mm, azabicyclo[2.2.1]heptan-2-yl)-4-((3S)-3- 5μ); mobile phase: 60:40(A:B), A = (cyanomethyl)-1-pyrrolidinyl)benzamide liquid CO2, B =methanol, flow rate: 4 ml/min; Sample load: 150 mg/30 mL (THF:MeOH =1:1), 8 mL/injection 2-48-2 2-chloro-N-((1R,2R,4S)-7-cyano-7- SFCMethod: Chiralpak IG (250 × 30 mm,azabicyclo[2.2.1]heptan-2-yl)-4-((3R)-3- 5μ); mobile phase: 60:40 (A:B),A = (cyanomethyl)-1-pyrrolidinyl)benzamide liquid CO2, B = methanol,flow rate: 4 ml/min; Sample load: 150 mg/30 mL (THF:MeOH = 1:1), 8mL/injection 2-43-2 2-chloro-N-((1R,2R,4S)-7-cyano-7- SFC Method:X-select C-18 (250 × 19 azabicyclo[2.2.1]heptan-2-yl)-4-((2R)-2- mm, 5μm); mobile phase. 0.1% ammonia cyano-6-azabicyclo[3.2.1]octan-6- inwater: ACN, flow rate: 1 ml/min; yl)benzamide Sample load: 20 mg/1 mL,0.25 mL/injection 2-61-2 2-chloro-N-((1R,2R,4S)-7-cyano-7- SFC Method:Lux C-4 (250 × 50 mm, 5μ); azabicyclo[2.2.1]heptan-2-yl)-4-((3S)-3-mobile phase: 50:50 (A:B), A = liquid(cyanomethyl)-1-piperidinyl)benzamide CO2, B = methanol, flow rate: 180ml/min; Sample load: 90 mg/10 mL, 5 mL/injection, 19 min runtime. 2-61-12-chloro-N-((1R,2R,4S)-7-cyano-7- SFC Method: Lux C-4 (250 × 50 mm, 5μ);azabicyclo[2.2.1]heptan-2-yl)-4-((3R)-3- mobile phase: 50:50 (A:B), A =liquid (cyanomethyl)-1-piperidinyl)benzamide CO2, B = methanol, flowrate: 180 ml/min; Sample load: 90 mg/10 mL, 5 mL/injection, 19 minruntime. 7-13-2 N-((1R,2R,4S)-7-cyano-7- SFC Method: Chiralpak AS-H (250× 21 azabicyclo[2.2.1]heptan-2-yl)-N-methyl-1- mm, 5 μm); mobile phase:85:15 (A:B), (2,3,5-trichlorophenyl)-L-prolinamide A = liquid CO2, B =methanol, flow rate: 120 ml/min; Sample load: 80 mg/10 mL, 3mL/injection 7-13-1 N-((1R,2R,4S)-7-cyano-7- SFC Method: Chiralpak AS-H(250 × 21 azabicyclo[2.2.1]heptan-2-yl)-N-methyl-1- mm, 5 μm); mobilephase: 85:15 (A:B), (2,3,5-trichlorophenyl)-D-prolinamide A = liquidCO2, B = methanol, flow rate: 120 ml/min; Sample load: 80 mg/10 mL, 3mL/injection 15-12-2 (1S,4R,5S)-N-((1R,2R,4S)-7-cyano-7- SFC Method:Column: Chiralpak AS-H azabicyclo[2.2.1]heptan-2-yl)-2-(3,5- (250 × 30mm, 5μ); mobile phase: 70:30 (A:B),dichlorophenyl)-2-azabicyclo[3.1.0]hexane-4- A = liquid CO2, B =methanol, flow carboxamide rate: 100 ml/min; Sample load: 50 mg/7 mLinjection 15-12-1 (1S,4S,5S)-N-((1R,2R,4S)-7-cyano-7- SFC Method:Column: Chiralpak AS-H azabicyclo[2.2.1]heptan-2-yl)-2-(3,5- (250 × 30mm, 5μ); mobile phase: 70:30 (A:B),dichlrophenyl)-2-azabicyclo[3.1.0]hexane-4- A = liquid CO2, B =methanol, flow carboxamide rate: 100 ml/min; Sample load: 50 mg/7 mLinjection 12-2-1 (1S,3S)-N-((1R,2R,4S)-7-cyano-7- The sample waspurified by SFC via an azabicyclo[2.2.1]heptan-2-yl)-3-(2,5- ChiralpakAY-H 2 × 25 cm, 5 μm column dichlorophenyl)cyclopentanecarboxamide amobile phase of 30% isopropanol using a flowrate of 60 mL/min 15-15-2(5R)-N-((1R,2R,4S)-7-cyano-7- The sample was purified by SFC using aazabicyclo[2.2.1]heptan-2-yl)-1-(6-(1,1- Chiralpak AD-H 2 × 25 cm, 5 umcolumn, a difluoroethyl)-2-pyridinyl)-4,5,6,7-tetrahydro- mobile phaseof 25% methanol using a 1H-indazole-5-carboxamide flowrate of 80 mL/min.to generate <1 mg of peak 1 with an ee of >99%, 3 mg of peak 2 with anee of >97%, 6 mg of peak 3 with an ee of >99% and 7 mg of peak 4 with anee of >99%. 15-16-2 (5R)-N-((1R,2R,4S)-7-cyano-7- The sample waspurified by SFC using a azabicyclo[2.2.1]heptan-2-yl)-1-(6- ChiralcelOJ-H 2 × 25 cm, 5 um column, a (difluoromethoxy)-2-pyridinyl)-4,5,6,7-mobile phase of 25% methanol using atetrahydro-1H-indazole-5-carboxamide flowrate of 80 mL/min. to generate2 mg of peak 1 with an ee of >99%, 3 mg of peak 2 with an ee of >99%, 6mg of peak 3 with an ee of >97% and 7 mg of peak 4 with an ee of >99%15-16-3 (5S)-N-((1R,2R,4S)-7-cyano-7- The sample was purified by SFCusing azabicyclo[2.2.1]heptan-2-yl)-2-(6-(1- Chiralpak AD-H 2 × 25 cm =Chiralpak cyanocyclopropyl)-2-pyridinyl)-4,5,6,7- AD-H 2 × 15 cm, 5 umcolumns, a mobile tetrahydro-2H-indazole-5-carboxamide phase of 35%methanol using a flowrate of 70 mL/min. 15-17-4(5R)-N-((1R,2R,4S)-7-cyano-7- The The sample was purified by SFC using aazabicyclo[2.2.1]heptan-2-yl)-2-(6- Chiralcel OJ-H 2 × 25 cm, 5 umcolumn, a (difluoromethyl)-2-pyridinyl)-4,5,6,7- mobile phase of 30%methanol using a tetrahydro-2H-indazole-5-carboxamide flowrate of 80mL/min

USP30 Enzymatic Assay (FP Assay)

Potency of USP30 (ubiquitin specific peptidase 30) inhibitors wasmeasured by their inhibition of human USP30 in a catalytic biochemicalassay. Purified human 6XHIS-USP30 (aa 57-517) was incubated with aK11-linked diubiquitin peptide substrate (UbiQ-044: UbiQ). On theN-terminus of the substrate is a fluorescent tag,5-carboxytetramethylrhodamine, which allows us to measure the cleavageof the substrate by fluorescence polarization. USP30 activity wasdetermined at room temperature in black 384-well microplates (Corning4514; Corning) in a total reaction volume of 15 μl. Compound in DMSO wasplated in a 22-point, 1:2 dose-response curve, across the 384-wellplate. Wells 23 and 24 were reserved for positive (enzyme and substratealone) and negative (substrate alone) reaction controls. Compound,enzyme, and substrate were diluted in assay buffer 20 mM Tris pH=8.0,100 mM NaCl, 0.005% Tween-20, and freshly thawed 1 mM DTT. All reagentswere prepared at a 3× working concentration. 5 ul of compound was addedto the assay plates followed by 5 ul of the enzyme solution and finally,5 ul of substrate solution. Plates were stored in a dark, humidifiedenvironment while the reaction proceeded for 75 minutes at roomtemperature. To stop the reaction, 5 ul of 80 mM MES, pH=5.0 was addedto the assay plates. Fluorescence polarization data was acquired on anEnVision plate reader (Perkin Elmer).

Samples were measured with an excitation wavelength of 531 nm andemission wavelengths of 595Pnm and 595Snm. Fluorescence polarizationvalues (in milliP) were calculated by the EnVision (Perkin Elmer)operating software according to the following formula: mPvalue=1000*(S−G*P)/(S+G*P), where S=<detector 2 or FP TAMRA Dual(1)channel 2>, P=<detector 1 or FP TAMRA Dual(1) channel 1>, andG=G-factor. Data was then uploaded into Screener software (GeneData AG).The amount of signal generated in the presence of compounds versus thatin the presence of DMSO vehicle alone (high control) was calculatedusing the formula: % control (POC)=(compound−average low)/(averagehigh−average low)*100. For IC50 determinations, data was fitted usingScreener based on a general 4-parameter equation(y=A+((B−A)/(1+((x/C){circumflex over ( )}D))), where A is the minimum y(POC) value, B is the maximum y (POC), C is the x (compoundconcentration) at the point of inflection and D is the slope factor).

USP30 Enzymatic Assay (Rhodamine Assay)

USP30 inhibition was tested with recombinant human USP30 (BostonBiochem) using the fluorescent substrate Ubiquitin-Rhodamine 110(UBPBio) in 1536-well format Compounds in DMSO were dispensed using aLabcyte Echo 550 (50 nl/well). 2 μl of 4 nM USP30 in 25 mM Hepes (pH7.5) 100 mM NaCl 0.01% Triton X-100 1 mM DTT was added to each well andincubated for 2 hr at room temperature. 6 μl of 53 nMUbiquitin-Rhodamine 110 in 25 mM Hepes (pH 7.5) 100 mM NaCl 0.01% TritonX-100 4 mM DTT 0.02% BSA was then added to each well and incubated foran additional 2 hr at room temperature. Fluorescence measurements wereobtained using an Envision 2105 (Perkin Elmer) with λ_(ex)=485 nm andλ_(em)=535 nm. USP30 with DMSO and buffer alone with DMSO were used fornormalization of 100% activity and 0% activity, respectively. ApparentIC₅₀ values were obtained using Graphpad Prism.

USP30 Ex# IC₅₀ (μM) 1-1 1.3 1-2 55.0 1-3 49.7 1-4 0.4 1-5 1.4 1-6 1.11-7 12.5 1-8 1.8 1-9 1.0 1-10 7.2 1-11 3.6 1-12 3.8 1-13 1.3 1-14 5.61-15 8.4 1-16 5.3 1-17 0.4 1-18 16.0 1-19 0.5 1-20 0.8 1-21 3.5 1-2210.1 1-23 2.3 1-24 1.9 1-25 4.3 1-26 8.8 1-27 3.3 1-28 0.3 1-29 1.4 1-303.4 1-31 2.7 1-32 1.7 1-33 9.1 1-34 2.0 1-35 13.6 1-36 0.1 1-37 1.5 1-381.1 1-39 0.3 1-40 3.6 1-41 2.0 1-42 0.7 1-43 0.5 1-44 0.4 1-45 1.1 1-466.0 1-47 5.9 1-48 8.2 1-49 6.9 1-50 4.7 1-51 1.4 1-52 0.1 1-53 0.7 1-545.7 1-55 1.1 1-56 3.1 1-57 0.6 1-58 2.1 1-59 0.2 1-60 0.9 1-61 1.2 1-620.4 1-63 0.7 1-64 0.5 2-1-2 0.4 3-1-2 12.1 4-1-4 19.8 4-2-1 >66.7 4-2-226.9 4-2-3 19.0 4-2-4 14.6 5-1 0.2 5-2 0.8 5-3 0.9 5-4 8.2 5-5 3.2 5-60.9 5-7 0.3 5-8 16.7 5-9 4.1 5-10 0.2 5-11 0.1 5-12 0.3 5-13 0.3 5-140.2 5-15 0.7 6-1 0.7 6-2 0.9 6-3 8.7 7-1 2.1 7-2 2.1 8-1 12.1 8-2 22.59-1 25.8 9-2 0.1 9-3 0.4 9-4 1.4 9-5 1.2 9-6 35.0 9-7 4.7 9-8 43.7 9-90.5 11-2 0.6 11-3 0.8 11-4 0.4 11-5 0.7 11-6 0.5 11-7 4.8 13-1 0.3 13-27.1 13-3 0.1 13-4 0.2 13-5 0.1 13-6 17.2 13-7 28.3 13-8 0.5 13-9 15.013-10 1.3 13-11 2.1 13-12 5.8 13-13 0.4 13-14 0.2 13-15 2.4 13-16 0.413-17 2.0 13-18 0.6 13-19 8.4 13-20 7.9 14-1 11.7 14-2 39.0 14-3 17.014-4 0.1 14-5 1.9 15-1 0.1 1-65 0.59 1-66 0.279 1-68-2 0.02 1-69 2.3151-70 1.623 1-71 0.126 1-72 1.269 1-73 0.729 1-74 2.947 1-75 0.334 1-760.971 1-77 0.026 1-78 4.115 1-79 16.4 1-80 18.1 1-81 1.194 1-82 9.371-83 23.9 1-84 28.7 1-85 14.5 1-86 29.0 1-87 4.113 1-88 0.421 1-89 25.91-90 2.82 1-91 2.083 1-92 3.29 1-93 4.35 1-94 0.798 1-95 3.883 1-966.515 1-97 0.061 2-2 2.37 2-3 0.716 2-4 14.5 2-5 9.8 2-6 31.0 2-7 10.52-8 36.9 2-9 0.245 2-10 0.987 2-11 0.253 2-12 3.53 2-13 33.868 2-140.191 2-15 32.415 2-16 0.392 2-17 0.108 2-18 0.273 2-19 0.157 2-20 0.1442-21 0.062 2-22 1.470 2-23 0.078 2-24-1 0.031 2-24-2 0.077 2-26 0.1962-27-2 1.880 2-27-1 1.270 2-29 1.650 2-30 1.800 2-31-2 0.305 2-31-20.091 2-33 0.279 2-34 2.790 7-35 9.840 2-36 0.207 2-37 0.815 2-38 2.6902-39-1 5.210 2-39-2 5.450 2-41 4.700 2-42 0.046 2-43-1 12.200 2-44 1.6602-45 0.126 2-46-2 0.604 2-46-3 14.800 2-48-1 2.290 2-48-2 1.510 7-502.250 2-51 1.810 2-52 0.161 2-43-2 3.460 2-54 1.210 2-55 0.096 7-565.790 2-57 1.190 2-58 4.080 2-59 0.232 2-60 0.444 2-61-2 2.060 2-61-12.020 2-63 0.027 2-64 0.083 2-65 0.076 2-66 0.078 2-67 1.580 5-16 0.2917-3 0.017 7-4 0.064 7-5 0.235 7-6 0.2 7-7 0.557 7-8 1.269 7-9 40.8 7-1010.7 7-11 0.272 7-12 0.318 7-13-2 0.138 7-13-1 2.080 7-15 0.022 7-160.125 7-17 0.037 7-18 0.829 9-1 7.67 9-2 16.7 9-3 4.58 9-4 0.23 9-50.286 9-6 0.113 12-3 0.211 12-4 0.417 12-5 0.057 12-6 0.01 12-7 30.412-8 0.381 12-9 0.079 12-10 0.064 12-11 0.056 12-12 0.065 12-13 0.27412-14 0.213 12-15 0.103 12-16 0.165 12-17 0.114 12-18 1.024 12-19 0.15112-20 0.393 12-21 0.034 12-22 0.192 12-23 0.054 12-24 0.04 12-25 0.02612-26 0.069 12-27 0.038 12-28 0.044 12-29 0.169 12-30 0.27 13-21 50.52913-22 0.402 13-23 2.257 13-24 0.762 13-25 0.115 13-26 3.267 13-27 0.92313-28 6.577 13-29 2.93 13-30 43.6 15-2 3.22 15-3 4.075 15-4 2.335 15-54.793 15-6 0.627 15-7 0.196 15-8 0.31 15-9 3.72 15-10 2.937 15-11 2.9415-12-2 0.048 15-12-1 0.448 15-14 0.257 15-15 0.057 15-16 0.456 16-324.8 16-4 1.78 16-5 1.635 20-1 3.26 20-2 2.24 20-3 0.06 20-4 0.055 20-50.065 20-6 0.055 20-7 0.028 20-8 0.254 20-9 0.124 20-10 0.194 20-11 0.0920-12 0.151 20-13 0.105 20-14 0.026 20-15 0.03 20-16 0.047 20-17 0.04920-18 3.293 20-19 0.407 20-20 0.177 20-21 2.047 20-22 0.519 20-23 0.31520-24 0.11 20-25 0.041 20-26 2.207 20-27 0.039 20-28 0.088 20-29 1.10520-30 0.103 20-31 14.9 20-32 0.447 20-33 1.438 20-34 0.783 20-35 1.65520-36 0.58 20-37 0.703 20-38 0.903 20-39 0.254 20-40 0.204 20-41 2.4120-42 3.715 20-43 0.247 20-44 0.221 20-45 0.241 20-46 0.235 20-47 0.09420-48 0.665 20-49 0.027 20-50 0.235 20-51 0.353 20-52 0.117 20-53 0.25220-54 0.121 20-55 0.201 20-56 0.098 20-57 0.479 20-58 1.284 20-59 0.92120-60 3.133 20-61 0.86 20-62 1.52 20-63 4.03 20-64 0.136 20-65 0.34520-66 37.7 20-67 0.192 20-68 0.058 20-69 0.39 20-70 0.328 20-71 1.59320-72 0.957 20-73 0.311 20-74 0.05 20-75 0.209 20-76 0.141 22-1 6.28523-1 0.148 23-2 0.121 23-3 0.129 23-4 0.486 23-5 0.212 23-6 0.114 23-70.562 23-8 0.118 23-9 0.36 24-1 0.114 25-1 2.04 25-2 1.482 25-3 0.37326-1-1 9.442 26-2-1 1.293 26-3 0.175 26-4 1.6 26-5 0.194 26-6 2.237 27-13.533 27-2 0.774 27-3 9.381 28-1 0.046 28-2 0.054 29-1 0.478 29-2 0.8129-3 0.097 29-4 0.294 29-5 0.058 29-6 2.09 29-7 0.029 30-1 2.663 30-25.89 30-3 0.88 30-4 0.037 30-5 2.155 30-6 0.029 30-7 0.025 30-8 0.12830-9 8.575 30-10 0.346 30-11 1.95 30-12 0.545 30-13 3.59 30-14 0.06230-15 0.35 30-16 0.192 30-17 0.054 31-1 5.87 31-2 8.87 32-1 0.044 32-20.135 32-3 3.8 32-4 0.133 32-5 0.064 32-6 0.139 33-1-1 1.52 33-1-2 0.0621-67-1 0.294 12-2-1 0.135 12-2-2 0.324 12-2-3 0.025 15-15-2 4.41715-16-2 0.701 15-16-3 1.76 15-15-3 8 15-16-3 0.609 15-15-4 0.704 15-16-42.647 15-17-4 13.35 17-1 4.16 18-1 0.872 19-1 0.152 21-1-1 1.98 21-1-21.84 21-1-3 3.39 21-1-4 0.904 21-2-3 0.52 21-2-4 4.26 20-77 0.05

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A compound or salt thereof, the compound according to the Formula(I):

Wherein D is (CR¹R²)_(r); r is 1 or 2; Each of R¹, R², R³, R⁴, R⁵, R⁶and R⁷ is independently selected at each occurrence from hydrogen,halogen, C₁-C₄alkyl, C₁-C₄alkoxy or C₃-C₆cycloalkyl; or R⁴ and R⁶ takenin combination form a fused three to six member cycloalkyl ring; or R⁴and R⁵ taken in combination form a spirocyclic three to six membercycloalkyl ring; R⁶ and R⁷ taken in combination form a spirocyclic threeto six member cycloalkyl ring; R⁸ is independently selected fromhydrogen or C₁-C₄alkyl; L is a bond or a divalent linker selected from—C(O)—, —C(O)N(R^(B))—, —N(R^(B))C(O)—, —N(R^(B))C(O)N(R^(B))—,—N(R^(B))S(O)_(p)—, —S(O)_(p)N(R^(B))—, —[C(R^(A))₂]_(q)C(O)N(R^(B))—,—C(O)N(R^(B))[C(R^(A))₂]_(q)—, —N(R^(B))C(O)N(R^(B))[C(R^(A))₂]_(q)—,—[C(R^(A))₂]_(q)N(R^(B))C(O)N(R^(B))—,—C(R^(A))₂N(R^(C))C(R^(A))₂C(O)N(R^(B))—,—N(R^(C))C(R^(A))₂C(O)N(R^(B))—, —C(O)N(R^(C))C(R^(A))₂C(O)N(R^(B))—,—N(R^(C))C(O)C(O)N(R^(B))—, —OC(R^(A))₂C(O)N(R^(B))— or—SC(R^(A))₂C(O)N(R^(B))—, wherein L is attached to the azanorbornane bythe right most atom; p is selected at each occurrence from 0, 1 or 2; qis 1, 2 or 3; R^(A) is independently, at each occurrence, hydrogen,C₁-C₄alkyl, haloC₁-C₄alkyl and haloC₁-C₄alkoxy, or C(R^(A))₂, taken incombination forms —C(O)— or 1,1-cyclopropandiyl; R^(B) is hydrogen orC₁-C₄alkyl; R^(C) is hydrogen, C₁-C₄alkyl or —C(R^(A))₂-A-B; A is adivalent moiety selected from C₂-C₆alkenylene, phenylene, naphthylene, 5to 13 member heteroarylene comprising one ring N, O or S atom and 0 or 1additional ring nitrogen atom, or saturated or partially unsaturated 4to 13 member monocyclic, bicyclic or tricyclic carbocycle or heterocyclecomprising one ring N, O or S atom and 0, 1 or 2 additional ringnitrogen atoms S, each of which is optionally substituted with 0 to 4substituents selected from halogen, hydroxy, oxo, amino, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₃-C₇cycloalkyl,C₃-C₇cycloalkoxy, C₃-C₇cycloalkylC₁-C₄alkyl, C₃-C₇cycloalkylC₁-C₄alkoxy,haloC₁-C₆alkyl, haloC₁-C₆alkoxy; B is hydrogen, halogen, hydroxy, amino,C₁-C₆alkyl, haloC₁-C₆alkyl, hydroxyC₁-C₆alkyl, cyanoC₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, haloC₁-C₆alkoxy,C₃-C₇cycloalkyl, halo C₃-C₇cycloalkyl, cyanoC₃-C₇cycloalkyl,C₃-C₇cycloalkylC₁-C₆alkyl, cyanoC₃-C₇cycloalkylC₁-C₆alkyl,C(O)C₁-C₆alkyl, C(O)C₃-C₇cycloalkyl, C(O)C₁-C₆alkyl,C(O)C₃-C₇cycloalkyl, NR⁹R¹⁰, OR¹¹, C(O)NR⁹R¹⁰, N(R¹⁰)C(O)R¹², phenyl,aralkyl, heteroaralkyl, 5, 6, 9 or 10 member heteroaryl or 4 to 8 membermonocyclic or bicyclic heterocycle, wherein each heteroaryl orheterocycle has one ring N, O or S atom and 0, 1 or 2 additional ringnitrogen atoms, which phenyl, aralkyl, heteroaralkyl, heteroaryl orheterocycle is optionally substituted with 0 to 4 groups independentlyselected from the group consisting of halogen, hydroxy, amino, mono- anddi-C₁-C₆alkylamino, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, halo C₁-C₆alkyl, halo C₁-C₆alkoxy, C₃-C₆cycloalkyl, phenyl,5 or 6 member heteroaryl having one ring N, O or S atom and 0, 1 or 2additional ring nitrogen atoms, —C(O)NR⁹R¹⁰, C(O)R⁹, CO₂R⁹, andS(O)_(n)R⁹, and where each heterocycle is optionally substituted withoxo; R⁹ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆alkoxy, halo C₁-C₆alkyl, halo C₁-C₆alkoxy, C₃-C₆cycloalkyl, aralkylwhich aralkyl is substituted with 1 to 4 substitutents independentlyselected from halogen, C₁-C₄alkyl, C₃-C₆cycloalkyl or1,1-cyclopropandiyl; R¹⁰ is hydrogen or C₁-C₆alkyl; R¹¹ isC₃-C₆cycloalkyl, phenyl or 5 or 6 member heteroaryl having one ringnitrogen atom and 0 or 1 additional ring heteroatoms selected from N, Oor S, which phenyl or heteroaryl is optionally substituted with 0, 1, 2,or 3 groups independently selected from halogen, cyano, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, halo C₁-C₆alkyl, haloC₁-C₆alkoxy, C₃-C₆cycloalkyl; and R¹² is selected from C₁-C₆alkyl,C₁-C₆alkoxy, halo C₁-C₆alkyl, halo C₁-C₆alkoxy, C₃-C₆cycloalkyl, phenylor 5 or 6 member heteroaryl having one ring nitrogen atom and 0 or 1additional ring heteroatoms selected from N, O or S, which phenyl orheteroaryl is optionally substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, hydroxy, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆alkoxy, halo C₁-C₆alkyl, halo C₁-C₆alkoxy,C₃-C₆cycloalkyl.
 2. (canceled)
 3. The compound of claim 1, whichcompound is represented by Formula Ia:


4. The compound of claim 1, wherein L is —C(O)N(R^(B))— and R^(B) ishydrogen, methyl or ethyl.
 5. The compound of claim 4 represented byFormula II:


6. The compound of claim 1, wherein the azanorbornane is in endoorientation.
 7. The compound of claim 1, represented by Formula II-a orII-b:


8. The compound of claim 1, wherein -A-B is selected from the groupconsisting of

Wherein * represents point of attachment to L; Each occurrence of Q isindependently selected from CR¹³ or N; R¹³ is 0, 1, 2 or 3 independentlyselected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆alkoxy,haloC₁-C₆alkyl, haloC₁-C₆alkoxy, C₃-C₆cycloalkyl,C₃-C₆cycloalkyC₁-C₄alkoxy, or C₃-C₆cycloalkylC₁-C₄alkyl.
 9. The compoundof claim 8, represented by Formula III:

Wherein R¹³ is 0, 1, 2 or 3 independently selected from hydrogen,halogen, hydroxy, amino, C₁-C₆alkyl, and C₁-C₆alkoxy; X is CH, CH₂,CH₂CH₂ or N; Y is CH, CH₂, CH₂CH₂, N or O; B is hydrogen, halogen,hydroxy, amino, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,C(O)C₁-C₄alkyl, C(O)C₃-C₅cycloalkyl, C(O)OC₁-C₄alkyl, C(O)NHC₁C₄alkyl orC(O)NHC₃-C₆cycloalkyl phenyl, 5 or 6 member heteroaryl or 5 or 6 memberheterocycle, wherein each heteroaryl or heterocycle has one ring N, O orS atom and 0, 1 or 2 additional ring nitrogen atom, which phenyl,heteroaryl or heterocycle is optionally substituted with 0 to 4 groupsindependently selected from the group consisting of halogen, hydroxy,amino, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, haloC₁-C₆alkyl, halo C₁-C₆alkoxy, C₃-C₆cycloalkyl, —C(O)NR⁹R¹⁰, C(O)R⁹,CO₂R⁹, S(O)_(n)R⁹; R⁹ is hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆alkoxy, halo C₁-C₆alkyl, halo C₁-C₆alkoxy,C₃-C₆cycloalkyl; and R¹⁰ is hydrogen or C₁-C₆alkyl.
 10. The compound ofclaim 9, wherein the compound is represented by Formula III-a or FormulaIII-b:


11. The compound of claim 9, wherein the compound is represented byFormula (III-c):

Wherein R¹³ is selected at each occurrence from the group consisting ofhydrogen, C₁-C₄alkyl, halogen, C₁-C₄alkoxy.
 12. The compound of claim 9,wherein the compound is represented by Formula III-d or Formula III-e:


13. The compound according to claim 7, wherein B is phenyl, pyridyl,pyrimidinyl or pyrazinyl each of which is optionally substituted with 0,1, or 2 independently selected from C₁-C₄alkyl, C₃-C₅cycloalkyl,cyanoC₁-C₄alkyl or cyanoC₃-C₅cycloalkyl; or B is C₁-C₆alkyl,C₃-C₆cycloalkyl, C(O)C₁-C₄alkyl, C(O)C₃-C₅cycloalkyl, C(O)OC₁-C₄alkyl,C(O)NHC₁C₄alkyl or C(O)NHC₃-C₆cycloalkyl.
 14. The compound according toclaim 7, represented by Formula IV:

Wherein R⁴ and R⁶ are each independently hydrogen or methyl; or R⁴ andR⁶, taken in combination form a fused cyclopropyl ring; R^(B) ishydrogen or methyl; Z is independently selected at each occurrence fromCH or N; W is CR¹⁴ or N, wherein 0, 1, or 2 occurrences of W and Z is Nand remainder is C; R¹³ is hydrogen, C₁-C₄alkyl or C₃-C₅cycloalkyl; R¹⁴is independently selected at each occurrence from hydrogen, C₁-C₄alkylor C₃-C₅cycloalkyl; X and Y are each CH₂; or X and Y are each selectedfrom CH or N such that at least one of X and Y is CH.
 15. The compoundof claim 14, wherein at least one occurrence of either R¹³ or R¹⁴ is nothydrogen.
 16. The compound of claim 14, wherein the azanorbornane is inthe endo conformation.
 17. The compound of claim 14, wherein thecompound is represented by Formula IV-a or Formula IV-b:


18. The compound of claim 9, represented by Formula V:

Wherein R⁴ and R⁶ are each independently hydrogen or methyl; or R⁴ andR⁶, taken in combination form a fused cyclopropyl ring; R⁸ is hydrogenor methyl; R¹⁵ is C₁-C₄alkyl, C₁-C₄alkoxy, C₃-C₅cycloalkyl,C₃-C₅cycloalkyloxy, C₃-C₅cycloalkylC₁-C₄alkyl,C₃-C₅cycloalkylC₁-C₄alkoxy; X and Y are each CH₂; or X and Y are eachselected from CH or N such that at least one of X and Y is CH.
 19. Thecompound of claim 18, wherein the azanorbornane is in the endoconformation.
 20. The compound of claim 19, wherein the compound isrepresented by Formula V-a or Formula V-b:


21. A compound or salt thereof according to claim 1, the compoundaccording to formula (VI)

Wherein G is O, S, N(R^(C)), *—C(O)N(R^(C)) or *—(CH₂)N(R^(C)), whereinthe * represents attachment to B-A-; R^(C) is hydrogen, C₁-C₄alkyl or—CH₂-A-B; A is phenyl, naphthylene, 5 or 6 member heteroaryl comprisingone ring nitrogen atom and 0 or 1 additional ring heteroatoms selectedfrom N, O or S, each of which is optionally substituted with 0 to 4substituents selected from halogen, hydroxy, amino, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, halo C₁-C₆alkyl, and haloC₁-C₆alkoxy; B is hydrogen, halogen, hydroxy, amino, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl,C(O)C₁-C₆alkyl, C(O)C₃-C₆cycloakyl, C(O)NR⁹R¹⁰, phenyl, 5 or 6 memberheteroaryl or 5 or 6 member heterocycle, wherein each heteroaryl orheterocycle has one ring N, O or S atom and 0, 1 or 2 additional ringnitrogen atom, which phenyl, heteroaryl or heterocycle is optionallysubstituted with 0 to 4 groups independently selected from the groupconsisting of halogen, hydroxy, amino, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆alkoxy, halo C₁-C₆alkyl, halo C₁-C₆alkoxy,C₃-C₆cycloalkyl, —C(O)NR⁹R¹⁰, C(O)R⁹, CO₂R⁹, S(O)_(n)R⁹.
 22. A compoundof claim 21, wherein G is O, S, N(H) or *C(O)N(H), wherein the *represents attachment to B-A-; A is phenyl, naphthyl or 5 or 6 memberheteroaryl, each of which is optionally substituted with 0, 1, 2, 3, or4 groups independently selected from the group consisting of halogen,hydroxy, amino, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,halo C₁-C₆alkyl, and halo C₁-C₆alkoxy.
 23. The compound of claim 21,which is a compound of Formula VII:

Wherein R^(B) is H or methyl; R⁴ and R⁶ are each independently hydrogenor methyl; or R⁴ and R⁶, taken in combination form a fused cyclopropylring; G is O, S, or N(H); R¹⁶ is halogen, hydroxy, amino, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, halo C₁-C₆alkyl, and haloC₁-C₆alkoxy.
 24. The compound of claim 21, wherein the azanorbornane isin the endo conformation.
 25. The compound of claim 21, wherein thecompound is represented by Formula VII-a or Formula VII-b:


26. A compound of claim 21, wherein G is *CH₂N(R^(C)), wherein the *represents attachment to B-A-; R^(C) is CH²-A-B; A is independentlyselected at each occurrence from phenyl, naphthyl or 5 or 6 memberheteroaryl, each of which is optionally substituted with 0, 1, 2, 3, or4 groups independently selected from the group consisting of halogen,hydroxy, amino, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,halo C₁-C₆alkyl, and halo C₁-C₆alkoxy; B is independently selected ateach occurrence from hydrogen, halogen, hydroxy, amino, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₃-C₆cycloalkyl,C(O)C₁-C₆alkyl, C(O)C₃-C₆cycloakyl, and C(O)NR⁹R¹⁰.
 27. The compound ofclaim 26, wherein A is independently selected at each occurrence fromphenyl, pyridyl or pyrimidinyl, each of which is optionally substitutedwith 0, 1, 2 or 3 groups independently selected from halogen, hydroxy,amino, C₁-C₆alkyl, C₁-C₆alkoxy, halo C₁-C₆alkyl, and halo C₁-C₆alkoxy.28. The compound of claim 21, which is a compound of Formula VIII:

Wherein R^(B) is H or methyl; R⁴ and R⁶ are each independently hydrogenor methyl; or R⁴ and R⁶, taken in combination form a fused cyclopropylring; A is independently selected at each occurrence from phenyl,pyridyl or pyrimidinyl, each of which is optionally substituted with 0,1, 2 or 3 groups independently selected from halogen, hydroxy, amino,C₁-C₆alkyl, C₁-C₆alkoxy, halo C₁-C₆alkyl, and halo C₁-C₆alkoxy.
 29. Thecompound of claim 26, wherein the azanorbornane is in the endoconformation.
 30. The compound of claim 26, wherein the compound isrepresented by Formula VIII-a or Formula VIII-b:


31. (canceled)
 32. (canceled)
 33. The compound of claim 1, in a form ofa pharmaceutically acceptable salt.
 34. A pharmaceutical compositioncomprising a pharmaceutically acceptable excipient, carrier or adjuvantand at least one compound of claim
 1. 35. A method of treating a diseaseor disorder mediated by USP30 in a mammal which method comprisesadministering to the mammal a therapeutically effective amount of atleast one compound of claim 1, or a pharmaceutical salt thereof or apharmaceutical composition thereof.
 36. A method of treating a diseaseor disorder mediated by mitochondrial dysregulation in a mammal whichmethod comprises administering to the mammal a therapeutically effectiveamount of at least one compound of claim 1, or a pharmaceutical saltthereof or a pharmaceutical composition thereof.
 37. The method of claim36, wherein the disease or disorder mediated by USP30 is selected fromthe group consisting of a CNS disorder, neurodegenerative disease,multiple sclerosis, mitochondrial myopathy, encephalopathy, lacticacidosis, stroke-like episodes, Leber's hereditary optic neuropathy,cancer, neuropathy, ataxia, retinitis pigmentosa, materianally inheritedLeigh syndrome, Danon disease, diabetes, diabetic nephropathy, metabolicdisorders, heart failure, ischemic heart disease leading to myocardialinfarction, psychiatric disease, schizophrenia, multiple sulfatasedeficiency, mucolipidosis II, mucolipidosis III, mucolipidosis IV,GMI-gangliosidosis, neuronal ceroid-lipofuscinoses, Alpers disease,Barth syndrome, Beta-oxidation defects, carnitine-acyl-carnitinedeficiency, carnitine deficiency, creatine deficiency syndromes,co-enzyme Q10 deficiency, complex I deficiency, complex II deficiency,complex III deficiency, complex IV deficiency, complex V deficiency, COXdeficiency, chronic progressive external ophthalmoplegia syndrome, CPT Ideficiency, CPT II deficiency, glutaric aciduria type II, Kearns-Sayresyndrome, lactic acidosis, long-chain acyl-CoA dehydrogenase deficiency,Leigh disease or syndrome, lethal infantile cardiomyopathy, Luftdisease, glutaric aciduria type II, medium-chain acyl-CoA dehydrogenasedeficiency, myoclonic epilepsy and ragged-red fiber syndrome,mitochondrial cytopathy, mitochondrial recessive ataxia syndrome,mitochondrial DNA depletion syndrome, myoneurogastointestinal disorderand encephalopathy, Stiff Person syndrome, pyruvate dehydrogenasedeficiency, pyruvate carboxylase deficiency, POLG mutations,medium/short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, verylong-chain acyl-CoA dehydrogenase deficiency, and age-dependent declinein cognitive function and muscle strength.
 38. The method of claim 37,wherein the neurodegenerative disease is selected from Parkinson'sdisease, Alzheimer's disease, amyotrophic lateral sclerosis,Huntington's disease, ischemia, stroke, dementia with Lewy bodies,frontotemporal dementia, autosomal recessive juvenile Parkinson'sdisease where parkin is mutated and Parkinson's disease related tomutations in a synuclein, parkin and PINK1.
 39. The method of claim 37,wherein the disease or disorder mediated by USP30 is Parkinson's disease40. A method for modulating USP30 activity in a mammal which methodcomprises administering to the mammal an amount of at least one compoundof claim 1, or a pharmaceutical salt thereof or a pharmaceuticalcomposition thereof to modulate USP30 activity in the mammal. 41.(canceled)
 42. (canceled)
 43. (canceled)
 44. (canceled)